Autophagy, hallmarked by the formation of double-membrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in early-stage carcinogenesis, autophagy inhibits inflammation and promotes genomic stability. Moreover, disruption of autophagy-related genes accelerates tumorigenesis in animals. However, autophagy may also act as a pro-survival mechanism to protect cancer cells from various forms of cellular stress. In cancer therapy, adaptive autophagy in cancer cells sustains tumor growth and survival in face of the toxicity of cancer therapy. To this end, inhibition of autophagy may sensitize cancer cells to chemotherapeutic agents and ionizing radiation. Nevertheless, in certain circumstances, autophagy mediates the therapeutic effects of some anticancer agents. Data from recent studies are beginning to unveil the apparently paradoxical nature of autophagy as a cell-fate decision machinery. Taken together, modulation of autophagy is a novel approach for enhancing the efficacy of existing cancer therapy, but its Janus-faced nature may complicate the clinical development of autophagy modulators as anticancer therapeutics.
Protein degradation and normal turnover of organelles are essential for cellular homeostasis. There are two major evolutionarily conserved intracellular pathways for protein degradation, namely, the ubiquitin–proteasome system and macroautophagy (hereafter referred to as ‘autophagy’). The former degrades short-lived proteins through an elaborate set of ubiquitinating enzymes and a multimeric protein complex known as the proteasome, whereas the latter degrades long-lived proteins in a lysosome-dependent manner (Figure 1) (Mizushima et al., 2008; Wu et al., 2010a). Autophagy is also involved in the removal of damaged organelles and protein aggregates. Autophagy, which literally means ‘to eat oneself’, is initiated by the nonselective seizing of cytosolic proteins and organelles such as mitochondria, endoplasmic reticulum, peroxisomes and ribosomes by an expanding membranous structure known as the phagophore or isolation membrane. The closure of phagophores sequestering these cytosolic cargos results in the formation of double-membrane bound autophagosomes (Mizushima et al., 2008). Autophagy may also occur in a selective fashion in which aggregated proteins and damaged mitochondria are recognized by specific receptors for incorporation into autophagosomes (Gu et al., 2004; Bjorkoy et al., 2005; Wild and Dikic, 2010). In the late stage of autophagy, autophagosomes fuse with lysosomes to form autolysosomes, in which the engulfed content is digested by acidic hydrolases and the engendered amino acids are shuttled back to the cytoplasm via lysosomal membrane permeases for reuse (Mizushima et al., 2008). In this way, autophagy acts as an important internal source of cellular energy through self-cannibalism, especially in time of nutrient deprivation.
Dysregulation of autophagy, which alters the rate of protein degradation and the metabolic state of the cells, has severe consequences and is associated with several pathophysiological conditions, such as cancer, infection, autoimmunity, inflammatory diseases, neurodegeneration and aging (Mizushima et al., 2008; Levine et al., 2011). In relation to carcinogenesis, malignant tissues very often exhibit altered level of autophagic activity. Moreover, autophagy is regulated by various well-established cancer-related signaling pathways (Figure 1). Nevertheless, a coherent understanding of the role of autophagy in the pathogenesis of cancer is still lacking. Depending on context, autophagy can act as a bona fide oncogenic or tumor-suppressing mechanism. In cancer therapy, the role of autophagy is also paradoxical, in which this cellular process may serve as a pro-survival or pro-death mechanism to counteract or mediate the cytotoxic effect of anticancer agents. In the major part of this review, we will discuss how autophagy is deranged in human cancers and its regulation by different oncogenic and tumor-suppressing pathways. We will also focus on the function of autophagy as a cell-fate decision machinery in the context of cancer therapy and explore possible factors that may affect the cellular outcome of autophagy.
Autophagy and cancer
Dysregulation of autophagy in human cancers
Autophagy is dysregulated in a wide spectrum of human cancers (Table 1). For instance, the altered expression of several autophagy markers such as microtubule-associated protein light chain 3 (LC3) and Beclin 1 has been reported in brain, esophageal, colon, gastric, liver and pancreatic cancers as well as osteosarcoma and melanoma. Mutations of various autophagy-related genes have also been documented in a subset of gastrointestinal cancers. Importantly, some of these abnormalities have been shown to correlate with clinicopathological parameters and disease outcomes including overall survival in cancer patients. These findings not only underscore a pivotal role of autophagy in tumorigenesis, but also highlight the possibility of using autophagy-associated molecules as novel prognostic markers in clinical settings (Russell et al., 1990; Eccles et al., 1992; Futreal et al., 1992; Cliby et al., 1993; Saito et al., 1993; Gao et al., 1995; Ahn et al., 2007; Miracco et al., 2007, 2010; Ding et al., 2008; Fujii et al., 2008; Yoshioka et al., 2008; Kim et al., 2008a; Kang et al., 2009; Lazova and Pawelek, 2009; Nomura et al., 2009; Othman et al., 2009; Pirtoli et al., 2009; Li et al., 2009, 2010; Zhang et al., 2009a; Huang et al., 2010; Koukourakis et al., 2010; Lazova et al., 2010; Miao et al., 2010; Negri et al., 2010; Sivridis et al., 2010; Wan et al., 2010; Karpathiou et al., 2010; Chang et al., 2011; Ma et al., 2011).
Regulation of autophagy by oncogenic and tumor-suppressing pathways
The importance of autophagy in carcinogenesis can also be underlined by the fact that this cellular process is meticulously regulated by many cancer-related signaling pathways.
The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a major oncogenic cascade. Abnormal activation of this pathway as a result of gain-of-function mutations or amplifications of the oncogenes PI3K and Akt as well as the loss of the tumor-suppressor phosphatase and tensin homolog (PTEN; an antagonist of PI3K) are frequently detected in tumor tissues. Somatic mutations of TSC1 (tuberous sclerosis protein 1), which is a negative regulator of mTOR, may also contribute to bladder and liver cancers (Platt et al., 2009; Totoki et al., 2011). In addition, heightened mTOR activity has been reported in many cancer types (Zhang et al., 2009b; Xu et al., 2010; Liu et al., 2011). The PI3K/Akt/mTOR cascade can also be transactivated by receptor tyrosine kinases that mediate the mitogenic signal of growth factor stimulation. The PI3K/Akt/mTOR pathway is a central repressor of autophagy. PTEN overexpression has been shown to promote autophagy (Arico et al., 2001), whereas the targeted deletion of PTEN in mouse liver causes a strong inhibition of autophagy (Ueno et al., 2008). Akt inhibition also strongly promotes autophagy whereas constitutively active Akt has the opposite action (Laane et al., 2009). Inhibitors of mTOR have also been shown to induce autophagy in various cell types (Paglin et al., 2005; Cao et al., 2006; Iwamaru et al., 2007). In addition, stabilization of TSC2, which inhibits the mTOR signaling, promotes autophagy and suppresses tumorigenesis (Kuo et al., 2010). The inhibitory effect of PI3K/Akt/mTOR axis on autophagy is mainly mediated through the ULK1/2 (unc-51-like kinase 1/2)/mAtg13/FIP200 (focal adhesion kinase family interacting protein of 200 kDa) complex (Ganley et al., 2009; Jung et al., 2009). Under growth-permissive conditions, mTOR inhibits the ULK1/2/mAtg13/FIP200 complex to repress autophagy. However, when the cells are deprived of growth factors or nutrients, mTOR dissociates from the ULK1/2/mAtg13/FIP200 complex, thereby unmasking the kinase activities of ULK1/2, leading to FIP200 phosphorylation and recruitment of Atg proteins to the autophagosome formation site. Although the link between mTOR inhibition and autophagy is well established, it is worthwhile to notice that in some situations, mTOR may stimulate autophagy. In this regard, Zeng and Kinsella (2008) demonstrated that mTOR and its downstream mediator S6 kinase 1 may positively regulate autophagy in 6-thioguanine-treated cells, possibly through the negative feedback inhibition of Akt.
Evasion of apoptosis is linked to the development of cancer. The antiapoptotic members (for example, Bcl-2, Mcl-1, Bcl-xL, Bcl-w, A1) of B-cell lymphoma 2 (Bcl-2) family are essential BH domain-containing proteins that exert their action through antagonism of pro-apoptotic members (for example, Bak and Bax). Growing evidence supports that, in addition to their antiapoptotic property, Bcl-2, Mcl-1 and Bcl-xL (B-cell lymphoma-extra large) are potent inhibitors of autophagy (Zhou et al., 2011). Beclin 1, the mammalian ortholog of Atg6, is a Bcl-2-interacting protein that exists in complexes of at least three different configurations (Beclin 1/hVps34/p150/Atg14, Beclin 1/hVps34/p150/UVRAG/Bif1 and Beclin 1/hVps34/p150/Rubicon/UVRAG). It is now known that the Atg14-containing complex functions at the early stage of autophagosome formation, whereas the UVRAG/Bif1-containing complex facilitates membrane curvature of autophagosomes. In contrast, the Rubicon/UVRAG-containing complex promotes the maturation phase (Yang and Klionsky, 2010). Regardless of the specific functions of these complexes, the interaction between hVps34 and Beclin 1 is required for autophagosome formation. Overexpression of Bcl-2 or Bcl-xL has been shown to disrupt hVps34/Beclin 1 interactions by sequestering Beclin 1 (Pattingre et al., 2005). Bcl-2 or Bcl-xL also inhibits the heterodimerization between UVRAG and Beclin 1 (Noble et al., 2008). Accordingly, overexpression of BH3 (Bcl-2 homology domain 3)-only proteins or addition of BH3 mimetics, which bind to antiapoptotic members of the Bcl-2 family through their BH domains, reduce the availability of Bcl-2 and Bcl-xL, thereby disinhibiting Beclin 1-dependent autophagy (Maiuri et al., 2007a).
Abnormal activation of the oncogenic Ras is frequently documented in cancer. Recent findings have revealed that active Ras may promote autophagy that, depending on the cellular context, limits or enables the oncogenic effect of Ras. Previous studies have reported that expressing active Ras in the absence of other cooperating mutations may induce proliferative arrest or senescence in some cell lines, indicating that increased Ras activity per se is insufficient to transform cells (Serrano et al., 1997; Yaswen and Campisi, 2007). In this regard, a recent study reported that human ovarian surface epithelial cells expressing HRASV12 undergo caspase-independent cell death with features of autophagy (Elgendy et al., 2011). In this connection, HRASV12-induced cell death is prevented by knockdown of Beclin 1 or Atg5, both of which are essential for the formation of autophagosomes in mammalian cells. Mechanistically, HRASV12 upregulates the expression of Beclin 1 through the downstream mitogen-activated protein kinase kinase (MEK)/extracellular-signal-regulated kinase (ERK) cascade. Meanwhile, HRASV12 induces the expression of Noxa (a BH3-only protein) that displaces Beclin 1 from Mcl-1 (a Bcl2 family member). The unopposed Beclin 1 then promotes autophagy that eventually leads to cell death. These findings suggest that autophagy as a tumor-suppressing mechanism may restrict Ras-induced oncogenesis, especially when other oncogenic signals are unavailable. Paradoxically, autophagy is also required for the survival of Ras-transformed cells. In immortalized baby mouse kidney (iBMK) cells, expression of HRASV12 or KRASV12 increases rates of basal autophagy, whereas genetic ablation of Atg5 or Atg7 impairs the tumorigenicity of these cells in nude mice (Guo et al., 2011). In Ras-expressing iBMK cells, defects in autophagy promote the accumulation of dysmorphic mitochondria, reduce oxygen consumption and cause depletion of tricarboxylic acid cycle metabolites. Consistent with these findings, Yang et al. (2011) demonstrated that treatment with the autophagy inhibitor chloroquine leads to prolonged survival in KRAS-driven genetic mouse model of pancreatic ductal adenocarcinoma. Genetic or pharmacologic inhibition of autophagy also reduces mitochondrial oxidative phosphorylation in pancreatic ductal adenocarcinoma cells. These findings indicate that autophagy enables Ras-induced oncogenesis by maintaining functional mitochondria and oxidative metabolism. The importance of the Ras/Raf/MEK/ERK cascade in the regulation of autophagy is further corroborated by the finding that hyperactivation of oncogenic BRAF induces autophagy whereas specific inhibition on MEK or depletion of ERK inhibits autophagy (Wang et al., 2009; Maddodi et al., 2010).
The TP53 tumor-suppressor gene, also known as the guardian of human genome, is mutated in ∼50% of human cancers. It encodes the 53 kDa phosphoprotein p53 that accumulates in cells in response to DNA damage, oncogene activation and other stresses. Activation of p53 induces DNA repair genes and arrests the cell cycle to allow enough time for fixation of DNA damage. Nevertheless, if DNA damage is beyond repair, p53 induces apoptosis to prevent accumulation of potentially oncogenic mutations. Accumulating evidence suggests that p53 can regulate autophagy in a dual fashion, the outcome of which depends on its subcellular localization (Maiuri et al., 2010). Nuclear p53 as a transcription factor stimulates autophagy through transcriptional upregulation of its pro-autophagic target genes, including damage-regulated autophagy modulator (DRAM; a lysosomal protein), Sestrin2, Skp2, PUMA, Bax, ULK1/2 and ISG20L1 (Crighton et al., 2006; Maiuri et al., 2009; Yee et al., 2009; Barre and Perkins, 2010; Eby et al., 2010; Gao et al., 2011). In addition, p53 promotes the dissociation of the Beclin 1/Bcl-2 complex and inhibits mTOR signaling (Feng and Levine, 2010; Lorin et al., 2010). In contrast to nuclear p53, cytoplasmic p53 exerts a negative regulatory effect on autophagy. In cells of different species, depletion or inhibition of p53 stimulates pro-survival autophagy that improves cellular fitness under conditions of hypoxia and nutrient depletion. Importantly, the pro-autophagic effect of p53 depletion can be reproduced in enucleated cells. Moreover, cytoplasmic, but not nuclear, p53 represses the enhanced autophagy in p53-deficient cells, indicating a transcription-independent inhibitory effect of p53 on autophagy (Tasdemir et al., 2008). In line with these findings, Morselli et al. (2008) have demonstrated that one-third mutants among a panel of 22 cancer-associated p53 mutants inhibit autophagy when transfected into p53−/− cells, in which most of these mutants preferentially localize to the cytoplasm. The regulation of autophagy by p53 has also been complicated by the finding that p53 post-transcriptionally downregulates LC3 during prolonged nutrient deprivation to enable a reduced, yet sustainable autophagic flux (Scherz-Shouval et al., 2010). To this end, p53 may increase cell fitness by maintaining better autophagic homeostasis that partially explains why some cancer cells retain wild-type p53.
Nuclear factor-κB (NF-κB) is a family of dimeric transcription factors. The most common form in human cells is the p50/RelA but other forms, such as p50/p50, p52/p52, p52/RelA, p50/c-Rel, c-Rel/c-Rel, p52/RelB and p50/RelB, have also been identified. This transcription factor is normally sequestered in the cytoplasm by its inhibitor IκB. Upon activation, IκB is phosphorylated by the IκB kinase (IKK) complex and subject to proteasomal degradation, causing the liberation and translocation of NF-κB into the nucleus where it alters gene expression. Activation of NF-κB is linked to inflammation and may be implicated in the pathogenesis of inflammation-associated cancers. In the past two decades, owing to the frequent detection of its activation in human cancers, much attention has been given to the oncogenic property of NF-κB. Nevertheless, recent evidence suggests that this transcription factor may also function as a tumor suppressor in some scenarios, for example, during liver carcinogenesis (Chen and Castranova, 2007). Evolving evidence demonstrates that NF-κB can positively regulate autophagy. For instance, RelA upregulates Beclin 1 through direct binding to the NF-κB-binding site on the Beclin 1 gene promoter to induce autophagy (Copetti et al., 2009). NF-κB-dependent upregulation of Beclin 1 is also responsible for the induction of pro-survival autophagy after heat shock (Nivon et al., 2009). Gangliosides and oridonin also activate NF-κB and autophagy in astrocytes and HT1080 cells, respectively, in which their pro-autophagic effects are blocked by specific NF-κB inhibitors (Hwang et al., 2010). In addition, NF-κB, in concert with p53, regulates autophagy through modulating the expression of its target gene Skp2 (Barre and Perkins, 2010). The multilevel control of autophagy by the IKK/IκB/NF-κB axis is also highlighted by the finding that IKK promotes the autophagic pathway in an NF-κB-independent manner. All these findings support the idea that NF-κB activation promotes autophagy (Criollo et al., 2010). Nevertheless, contrary evidence also exists in the literature. It has been shown that NF-κB represses tumor necrosis factor-α-induced autophagy in Ewing sarcoma cells through activation of mTOR (Djavaheri-Mergny et al., 2006). The reason for these discrepancies remains unclear, but it is possible that the dimeric composition of NF-κB, as in other physiological contexts, may determine the functional outcome of NF-κB activation (Bren et al., 2001; Lovas et al., 2008).
Cyclin-dependent kinase inhibitors and E2F1
E2F1 is a pivotal transcription factor that controls cell proliferation through inducing a number of genes required for G1–S transition. Paradoxically, E2F1 may in some scenarios facilitate cell cycle arrest and apoptosis. Thus, E2F1 displays dual functions of an oncogene and a tumor-suppressor protein. In growth-arrested cells, the transcriptional activity of E2F1 is inhibited by its binding partner retinoblastoma protein (pRB), whose degradation depends on its phosphorylation by cyclin-dependent kinases (CDK) 4 and 6. The activity of CDK 4 and 6 are in turn controlled by the relative abundance of G1 cyclins (cyclin D, cyclin E) and CDK inhibitors (p15, p16, p18, p19, p21, p27). E2F1 is recently shown to be linked to autophagy in which, depending on cellular context, this transcription factor may positively or negatively regulate autophagy. In U2OS osteosarcoma cells, Polager et al. (2008) demonstrated that E2F1 binds to the promoter regions of Atg1, LC3 and DRAM and enhances their expression. E2F1 also indirectly increases Atg5 expression. Overexpression of E2F1 increases the number of LC3-positive autophagosomes, whereas RNA interference targeting E2F1 abolishes DNA damage-induced autophagy. In contrast to this finding, Jiang et al. (2010a) reported that overexpression of pRB, which antagonizes E2F1, induces autophagy in various cell lines accompanied with increased mRNA expression of Atg4a and Atg7. pRB mutants with impaired binding to E2F are deficient for autophagy induction whereas enforced expression of E2F1 antagonizes pRB-mediated autophagy. It has also been shown that two CDK inhibitors (that is, p16 and p27) are able to enhance autophagic activity. The authors postulated that the pro-autophagic effect of pRB is mediated through repression of E2F1-dependent Bcl-2 expression (Jiang et al., 2010b). In line with these findings, several groups of investigators have demonstrated that ectopic expression of p27 or stabilization of p27 by targeting the E3 ligase Spk2 is sufficient to induce autophagy (Komata et al., 2003; Liang et al., 2007; Chen et al., 2008). As opposed to p27, the role of another CDK inhibitor p21 is more equivocal. Although p21 has been shown to impair C(2)-ceramide- and CD40-induced autophagic activity, enforced expression of cytoplasmic p21 induces autophagy (Fujiwara et al., 2008; Portillo et al., 2010; Yang et al., 2010). These findings indicate that, similar to p53, the regulatory effect of p21 on autophagy may depend on its subcellular localization.
LKB1 is a tumor suppressor that is mutated in the Peutz–Jeghers cancer syndrome. Somatic mutations of LKB1 are also observed in non-small cell lung carcinoma (Sanchez-Cespedes, 2007). LKB1 activates the downstream adenine monophosphate-activated protein kinase (AMPK) to control cell proliferation and apoptosis under metabolic stress conditions. It has been demonstrated that activation of the LKB1/AMPK energy-sensing cascade stimulates autophagic activity through multiple pathways, including stabilization of p27 (Liang et al., 2007), repression of mTOR signaling (Alexander et al., 2010) and direct phosphorylation of ULK1 (Egan et al., 2011; Kim et al., 2011). In addition to metabolic stress, AMPK signaling is regulated by multiple upstream signaling components. For instance, the LKB1/AMPK cascade mediates the pro-autophagic effect of reactive oxygen species-dependent activation of ATM (ataxia telangiectasia mutated; Alexander et al., 2010). Independent of LKB1, transforming growth factor-β activated kinase 1 (TAK1) activates AMPK to induce cytoprotective autophagy in TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-treated epithelial cells (Herrero-Martin et al., 2009). LKB1/AMPK is also downstream of calmodulin-dependent kinase kinase-β that mediates autophagy induced by elevation of intracellular Ca2+ levels (Hoyer-Hansen and Jaattela, 2007).
Transforming growth factor-β
Transforming growth factor (TGF)-β is a cytokine with pleiotropic actions. In early-stage carcinogenesis, TGF-β signaling suppresses tumor formation by inhibiting cell proliferation or by inducing cell differentiation and apoptosis. However, in later stages of cancer, TGF-β signaling promotes cancer progression by fostering cell motility and invasiveness, angiogenesis and immune evasion. A recent study has demonstrated that TGF-β signaling induces autophagy in cancer cells. In hepatocellular carcinoma cells, TGF-β induces accumulation of autophagosomes and the lipidation of LC3 and enhances the degradation of long-lived proteins. TGF-β also enhances the expression of Beclin 1, Atg5, Atg7 and death-associated protein kinase (DAPK), the latter of which is a calmodulin-regulated serine/threonine kinase that possesses tumor-suppressing property. The induction of autophagy by TGF-β in hepatocellular carcinoma cells can be abolished by knockdown of Smad2/3, Smad4 or DAPK as well as pharmacological inhibition of c-Jun N-terminal kinase, indicating the involvement of both Smad and non-Smad signals (Kiyono et al., 2009). In addition to cancer cells, TGF-β has been shown to induce autophagy in mammary and renal epithelial cells as well as mesangial cells (Gajewska et al., 2005; Ding et al., 2010; Koesters et al., 2010).
Other tumor suppressors
The ARF (alternate reading frame) tumor-suppressor protein activates p53 through antagonism of Mdm2, the ubiquitin ligase that targets p53 for proteasome-dependent degradation. Evolving evidence supports that ARF is linked to autophagy through p53-dependent and p53-independent mechanisms. On the one hand, the full-length ARF induces p53 activation to promote autophagy. In this respect, ARF-mediated autophagy can be attenuated by knockdown of p53 (Abida and Gu, 2008). On the other hand, initiation of translation at alternative start codon on ARF mRNA gives rise to a short isoform known as short mitochondrial ARF. The short mitochondrial ARF causes dissipation of mitochondrial membrane potential and induces autophagic cell death that can be prevented by knockdown of Atg5 and Beclin 1 (Reef et al., 2006). The pro-autophagic effect of short mitochondrial ARF is known to be enhanced by the mitochondrial p32 protein that stabilizes short mitochondrial ARF but not the full-length ARF (Reef et al., 2007). It has been shown that the full-length ARF that normally resides in the nucleolus is incapable of inducing p53-independent autophagy (Reef and Kimchi, 2008).
Rab7 is a late endosome/lysosome-associated small GTPase that is involved in endosomal sorting, biogenesis of lysosome and phagocytosis. Rab7 is also a potential tumor suppressor. The RAB7 gene is located in a region that is frequently deleted in solid tumors (Kashuba et al., 1997). Dominant-negative Rab7 also cooperates with E1A to promote the transformation of p53-deleted mouse embryonic fibroblasts. In this connection, Rab7 inhibition prolongs cell survival after growth factor withdrawal by preventing the clearance of glucose and amino-acid transporter proteins from the cell surface (Edinger et al., 2003). Stable knockdown of Rab7 also promotes cell invasion whereas overexpression of Rab7 has an opposite effect (Steffan and Cardelli, 2010; Steffan et al., 2010). It has been demonstrated that Rab7 plays a role in the final maturation of late autophagic vacuoles and is essential for the normal progression of autophagy in mammalian cells (Gutierrez et al., 2004; Jager et al., 2004). In this regard, Rab7 associates with the membrane of autophagic vesicles and through its effector FYCO-1 (FYVE and coiled-coil domain containing 1) promotes the transport of autophagosomes along microtubule tracks to fuse with late endosomes or lysosomes (Pankiv and Johansen, 2010; Pankiv et al., 2010).
Tumor-suppressing and oncogenic action of autophagy
As a housekeeping mechanism, autophagy is involved in the elimination of damaged organelles, the failure of which may lead to cellular dysfunction and, eventually, tumorigenesis. For example, removal of damaged mitochondria by autophagy reduces the production of reactive oxygen species that lead to genomic instability (Gu et al., 2004; Mathew et al., 2007; Stenmark, 2010). Autophagy also promotes oncogene-induced cellular senescence and restricts necrosis that is associated with inflammation and accelerated tumor growth (Degenhardt et al., 2006; Narita and Young, 2009; Young et al., 2009). In two different animal models, monoallelic loss of Beclin 1 promotes the development of spontaneous malignancies and hepatitis B virus-induced premalignant lesions whereas mice deficient in Atg4C/autophagin-3 show an increased susceptibility to develop carcinogen-induced fibrosarcomas (Yue et al., 2003; Marino et al., 2007). Autophagy has also been shown to promote cancer cell death or cell cycle arrest induced by various tumor suppressors, such as, FoxO1 (forkhead box protein O1), EphB2 (ephrin receptor B2) and TGF-β (Kandouz et al., 2010; Suzuki et al., 2010; Zhao et al., 2010). A recent study also demonstrated that activation of autophagy inhibits invasion and migration of MDA-MB-231 cells, in which the effect could be blocked by LC3 silencing, suggesting that autophagy may negatively regulate cancer invasiveness (Indelicato et al., 2010).
As an oncogenic process, autophagy has been exploited by cancer cells to sustain tumor growth and survival, especially in time of nutrient deprivation or other stressful conditions. In this regard, autophagy protects cancer cells against various forms of cellular insults, including endoplasmic reticulum stress, loss of contact with the extracellular matrix and toxicities of cancer therapy (Fung et al., 2008; Levine and Kroemer, 2008; Wu et al., 2010b). Using Cre-mediated excision, Altman et al. (2011) showed that Atg3 deletion prevents BCR-Abl-mediated leukemogenesis. To this end, autophagy is essential to suppress a stress response that leads to p53 phosphorylation and upregulation of p21 and PUMA. Autophagy may also contribute to tumor dormancy. For instance, ARHI enables human ovarian cancer cells grown in mice to become dormant by inducing pro-survival autophagy (Lu et al., 2008). In addition, autophagy facilitates glycolysis and helps to maintain functional mitochondria and thus oxidative phosphorylation to satisfy the metabolic requirement of oncogene-induced transformation (Guo et al., 2011; Lock et al., 2011).
Autophagy and its outcome determinants in cancer therapy
Autophagy is induced by different forms of cancer therapy, including conventional chemotherapeutic drugs, novel targeted cancer therapeutics and ionizing radiation, in various types of solid and hematological malignancies (Table 2) (Han et al., 2007, 2008; Kim et al., 2007, 2008b, 2009a; Maiuri et al., 2007b; Kamitsuji et al., 2008; Meschini et al., 2008; Qadir et al., 2008; Turcotte et al., 2008; Fu et al., 2009; Lorin et al., 2009; Tormo et al., 2009; Fan et al., 2010; Gupta et al., 2010; Huang and Sinicrope, 2010; Li and Fan, 2010; Voss et al., 2010; Yacoub et al., 2010; Wu et al., 2010c; Lian et al., 2011; O’Donovan et al., 2011). In some circumstances, autophagy mediates the cytotoxic or cytostatic effect of anticancer agents, in which blockade of autophagy abolishes the therapeutic actions. On the other hand, autophagy can be triggered as a pro-survival response to withstand the toxicity of the therapy. In this case, inhibition of autophagy enhances drug- or radiation-induced cytotoxicity or cytostasis. However, in some scenarios, autophagy is merely a bystander whose induction or inhibition does not interfere with cell death or survival. The molecular mechanisms governing the switch between these different modes of action remain largely elusive but recent findings have shed new light on several factors that may potentially affect the cell-fate decision process of autophagy.
The genetic composition of cancer cells may play a deterministic role in controlling the functional outcome of autophagy. For instance, autophagy has been shown to protect HCT116 colon cancer cells and DU145 prostate cancer cells against cell death caused by inducers of endoplasmic reticulum stress, such as A23187, tunicamycin, thapsigargin and brefeldin A, whereas autophagy contributes to cell death in normal colonic epithelial cells and in the nontransformed murine embryonic fibroblasts treated by the same chemicals (Ding et al., 2007). Impairment of autophagy by dominant-negative Vps34, the class III PI3K, also induces apoptotic cell death in neuroblastoma cells expressing a C98X vasopressin mutant but not in the wild-type vasopressin-expressing counterpart (Castino et al., 2008). Moreover, the pan-Bcl-2 inhibitor (–)-gossypol paradoxically induces cytoprotective autophagy in MCF-7 breast cancer cells but autophagic cell death in glioma cells, in which the effects on cell viability can be blocked by RNA interference against Beclin 1 and Atg5 in both cases (Gao et al., 2010; Voss et al, 2010). The molecular mechanism underlying these disparities is presently unknown, but it is speculated that these cells may differentially express some proteins with cell death- or cell survival-specific function in autophagy. In agreement with this notion, a protein known as Draper has been shown to be required for autophagic cell death during the development of salivary gland in Drosophila but not autophagic survival in larval fat body cells following starvation (McPhee et al., 2010). It is believed that similar cell fate-specific proteins are conserved in human and may contribute to the decision between life and death during autophagy in cancer therapy.
Growth factor stimulation
Apart from the genetic composition of cancer cells, growth factor stimulation also significantly affects the cellular consequence of autophagy. For example, various cytokines and growth factors, including interleukin-1, macrophage colony-stimulating factor, insulin growth factor-1, heregulin, interleukin-8 and vascular endothelial growth factor, significantly rescue ARHI-induced reduction of colony formation in autophagic ovarian cancer cells, although by themselves they have no effect on the colony-forming ability of control cells. Exposure of cells to different extracellular matrix components, including poly-D-lysine, poly-L-lysine and fibronectin, also produces a similar effect (Lu et al., 2008). In another study, the chemokine MCP-1 (monocyte chemoattractant protein-1) protects prostate cancer cells from rapamycin-induced autophagic cell death by upregulating survivin expression (Roca et al., 2008). Moreover, in many circumstances, deprivation of growth factor signals by itself triggers autophagy (Lum et al., 2005; Altman et al., 2009). These findings highlight the importance of growth factor signals in the modulation of the functional consequence of autophagy.
As a crucial metabolic response at the cellular level, autophagy is regulated by multiple signaling pathways in a widely interacting manner. Emerging evidence supports the concept that the pro-survival or pro-death nature of autophagy may be pathway specific. For instance, curcumin, a natural phytochemical that is used as a chemoprophylactic agent, induces autophagy in cancer cells through concurrent activation of ERK1/2 and inactivation of the Akt/mTOR pathway. Although Akt activation and ERK1/2 inhibition both abolish curcumin-induced autophagy, only the former attenuates the cytotoxicity of curcumin. In contrast, ERK1/2 inhibition induces apoptotic cell death, suggesting that the cellular outcome of autophagy may be determined by the pathway that initiates autophagy (Aoki et al., 2007). This finding also reiterates the importance of pro-survival signaling in cell-fate decision during autophagy as ERK1/2 is a common mediator of growth factor stimulation.
Extent of autophagy
The level of autophagy has also been proposed to determine the die-or-survive decision of autophagy. Kang et al. (2007) found that in Caenorhabditis elegans, physiological levels of autophagy act to promote survival during starvation, whereas insufficient or excessive levels of autophagy render C. elegans starvation hypersensitive and lead to death. It is believed that unrestrained autophagy or unwarranted activation of autophagy in the midst of nutritional abundance may result in premature exhaustion of internal feeding materials, thereby making the cell vulnerable in face of real nutritional challenges. Excessive autophagy may also compromise the integrity of lysosomal membrane, resulting in the release of cathepsins into the cytosol (Park et al., 2008; Hsu et al., 2009; Bhoopathi et al., 2010). In fact, lysosomal membrane permeabilization (LMP) may underlie the therapeutic actions of some pro-autophagic drugs, such as temozolomide and brevinin-2R (Mathieu et al., 2007; Ghavami et al., 2008). The causational relationship between autophagy and LMP is exemplified by the finding that inhibition of resveratrol-induced autophagy by wortmannin or asparagine results in reduced LMP and resveratrol-associated cytotoxicity (Hsu et al., 2009). The induction of Atg5 and Beclin 1 together with formation of LC3-positive autophagosomes have also been shown to precede lysosomal dysfunction, cathepsin activation and cell death in cells treated with OSU-03012, a celecoxib derivative (Park et al., 2008). Cathepsin B also facilitates autophagy-mediated apoptosis in SPARC (secreted protein, acidic and rich in cysteine)-overexpressed primitive neuroectodermal tumor cells (Bhoopathi et al., 2010). These findings suggest that LMP may be an effector pathway of autophagic cell death, the blockade of which may prevent cellular demise. Nevertheless, it is noteworthy that the linkage from autophagy to LMP is not always unidirectional. In this regard, some lysosomotropic detergents, such as siramesine, which trigger cell death via a direct destabilization of lysosomes, have been shown to induce cytoprotective accumulation of autophagosomes (Ostenfeld et al., 2008).
There are some situations in which induction of autophagy only acts as a bystander, whose inhibition does not enhance or attenuate cell survival. In this respect, Bcl-2, an inhibitor of both apoptosis and autophagy, may limit both the pro-death and pro-survival action of autophagy. In growth factor-deprived conditions, autophagy sensitizes cells with moderate Bcl-2 expression to apoptosis. However, inhibition of autophagy by Atg5- or Beclin 1 short hairpin RNA has no effect on the survival of apoptosis-resistant, high Bcl-2-expressing cells, although these cells undergo a similar extent of autophagy upon growth factor withdrawal (Altman et al., 2009). In line with this notion, silencing of Bcl-2 expression by small interfering RNA (siRNA) induces autophagic cell death in breast cancer cells, in which knockdown of Atg5 significantly inhibits Bcl-2 siRNA-induced loss of cell viability (Akar et al., 2008). Concurrent inhibition of Bcl-2 by ABT-737 and induction of autophagy by rapamycin, a mTOR inhibitor, also significantly enhance the therapeutic effect of ionizing radiation in non-small cell lung tumor xenograft model (Kim et al., 2009b). During pro-survival autophagy, inhibition of Bcl-2 by the natural BH3 mimetic gossypol has also been shown to sensitize cancer cells to apoptosis following suppression of autophagy by wortmannin or Vps34, Atg5 or Beclin 1 short hairpin RNAs (Gao et al., 2010). It is therefore suggested that Bcl-2, in some circumstances, may mask the functional consequences of autophagy, either cell death or survival, with or without the effect on the formation of autophagosomes.
Choice of autophagy inhibitors
The complexity of the duality problem of autophagy is further increased by the fact that using different methods to inhibit autophagy could lead to entirely different outcomes. There are two major approaches, namely pharmacological inhibitors and RNA interference, to inhibit autophagy in the context of cancer therapy, both of which have been widely adopted by investigators in the field. The former consists of the use of chloroquine and bafilomycin A1, which interfere with lysosomal functions and prevent autophagy at the late stage. The RNA interference approach encompasses the use of siRNA or short hairpin RNA that knocks down proteins core to the autophagic machinery, including Vps34, LC3, Atg5, Atg7 and Beclin 1. In addition, some investigators use embryonic fibroblasts derived from Atg5- or Atg7-knockout mice to corroborate results derived from the former approaches.
In the literature, there are many instances in which the use of different inhibitors or the selection of different knockdown targets results in conflicting results. For example, inhibition of imatinib-induced autophagy by Atg5 siRNA attenuates imatinib-induced cytotoxicity whereas inhibition of autophagy by bafilomycin A1 enhances imatinib-induced cytotoxicity (Shingu et al., 2009). In hepatoma cells, LC3 siRNA, but not Atg5 or Beclin 1 siRNAs, abolishes concanavalin A-induced cell death (Chang et al., 2007). These disparities can be partly attributed to the limitation that lysosomotropic agents, such as bafilomycin A1 and chloroquine, may interfere with other lysosome-dependent cellular processes, including endosomal transport and nonautophagic lysosome-dependent cell death. As for the RNA interference approach, LC3 can have autophagy-independent function whereas autophagy can occur independent of Beclin 1 and Atg5/Atg7 (Scarlatti et al., 2008; Nishida et al., 2009; de Haan et al., 2010). Atg5 is also involved in calpain-induced apoptotic cell death (Yousefi et al., 2006). It is therefore recommended that multiple approaches should be used to confirm the role of autophagy.
Concluding remarks and future perspectives
Dysregulation of autophagy, a process regulated by many cancer-related signaling pathways and involved in both tumor suppression and oncogenesis, is a common phenomenon in human cancers. In cancer therapy, autophagy is induced in cancer cells as an adaptive response to promote cell survival. However, in certain circumstances, autophagy is required for the cytotoxic effect of some anticancer agents. As modulation of autophagy represents a novel approach for enhancing the therapeutic efficacies of cancer therapy, research efforts have been put forth to identify agents that induce or inhibit autophagy. Several FDA (Food and Drug Administration)-approved drugs have been identified as inducers (for example, rapamycin, fluspirilene, trifluoperazine, pimozide, niguldipine, nicardipine and amiodarone, loperamide) or inhibitors (for example, chloroquine, hydroxychloroquine, verteporfin) of autophagy (Zhang et al., 2007; Donohue et al., 2011). The toxicological and pharmacokinetic profiles of these agents are well established and, therefore, these agents can be easily incorporated into existing regiments of cancer therapy. Nevertheless, the molecular mechanism governing cell-fate decision during autophagy is still poorly understood and the Janus-faced nature of autophagy may complicate the clinical development of its modulators. It is important to determine if the pro-death or pro-survival action of autophagy is associated with a particular class of cancer therapeutics. Moreover, blockade of growth factor signals may enhance the therapeutic outcome of autophagy modulators. It is anticipated that, with more information on the cell fate-specific proteins or pathways essential to autophagy in human, the mystery of the autophagic paradox will be unlocked. Until then, the successful application of autophagy modulators as cancer therapeutics in clinical settings is more hype than hope.
Abida WM, Gu W . (2008). p53-Dependent and p53-independent activation of autophagy by ARF. Cancer Res 68: 352–357.
Ahn CH, Jeong EG, Lee JW, Kim MS, Kim SH, Kim SS et al. (2007). Expression of beclin-1, an autophagy-related protein, in gastric and colorectal cancers. APMIS 115: 1344–1349.
Akar U, Chaves-Reyez A, Barria M, Tari A, Sanguino A, Kondo Y et al. (2008). Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy 4: 669–679.
Alexander A, Cai SL, Kim J, Nanez A, Sahin M, MacLean KH et al. (2010). ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci USA 107: 4153–4158.
Altman BJ, Jacobs SR, Mason EF, Michalek RD, Macintyre AN, Coloff JL et al. (2011). Autophagy is essential to suppress cell stress and to allow BCR-Abl-mediated leukemogenesis. Oncogene 30: 1855–1867.
Altman BJ, Wofford JA, Zhao Y, Coloff JL, Ferguson EC, Wieman HL et al. (2009). Autophagy provides nutrients but can lead to Chop-dependent induction of Bim to sensitize growth factor-deprived cells to apoptosis. Mol Biol Cell 20: 1180–1191.
Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB, Kondo Y . (2007). Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol 72: 29–39.
Arico S, Petiot A, Bauvy C, Dubbelhuis PF, Meijer AJ, Codogno P et al. (2001). The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 276: 35243–35246.
Barre B, Perkins ND . (2010). The Skp2 promoter integrates signaling through the NF-kappaB, p53, and Akt/GSK3beta pathways to regulate autophagy and apoptosis. Mol Cell 38: 524–538.
Bhoopathi P, Chetty C, Gujrati M, Dinh DH, Rao JS, Lakka S . (2010). Cathepsin B facilitates autophagy-mediated apoptosis in SPARC overexpressed primitive neuroectodermal tumor cells. Cell Death Differ 17: 1529–1539.
Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A et al. (2005). p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171: 603–614.
Bren GD, Solan NJ, Miyoshi H, Pennington KN, Pobst LJ, Paya CV . (2001). Transcription of the RelB gene is regulated by NF-kappaB. Oncogene 20: 7722–7733.
Cao C, Subhawong T, Albert JM, Kim KW, Geng L, Sekhar KR et al. (2006). Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res 66: 10040–10047.
Castino R, Thepparit C, Bellio N, Murphy D, Isidoro C . (2008). Akt induces apoptosis in neuroblastoma cells expressing a C98X vasopressin mutant following autophagy suppression. J Neuroendocrinol 20: 1165–1175.
Chang CP, Yang MC, Liu HS, Lin YS, Lei HY . (2007). Concanavalin A induces autophagy in hepatoma cells and has a therapeutic effect in a murine in situ hepatoma model. Hepatology 45: 286–296.
Chang YT, Tseng HC, Huang CC, Chen YP, Chiang HC, Chou FP . (2011). Relative down-regulation of apoptosis and autophagy genes in colorectal cancer. Eur J Clin Invest 41: 84–92.
Chen F, Castranova V . (2007). Nuclear factor-kappaB, an unappreciated tumor suppressor. Cancer Res 67: 11093–11098.
Chen Q, Xie W, Kuhn DJ, Voorhees PM, Lopez-Girona A, Mendy D et al. (2008). Targeting the p27 E3 ligase SCF(Skp2) results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy. Blood 111: 4690–4699.
Cliby W, Ritland S, Hartmann L, Dodson M, Halling KC, Keeney G et al. (1993). Human epithelial ovarian cancer allelotype. Cancer Res 53: 2393–2398.
Copetti T, Bertoli C, Dalla E, Demarchi F, Schneider C . (2009). p65/RelA modulates BECN1 transcription and autophagy. Mol Cell Biol 29: 2594–2608.
Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR et al. (2006). DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126: 121–134.
Criollo A, Senovilla L, Authier H, Maiuri MC, Morselli E, Vitale I et al. (2010). The IKK complex contributes to the induction of autophagy. EMBO J 29: 619–631.
de Haan CA, Molinari M, Reggiori F . (2010). Autophagy-independent LC3 function in vesicular traffic. Autophagy 6: 994–996.
Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G et al. (2006). Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10: 51–64.
Ding WX, Ni HM, Gao W, Hou YF, Melan MA, Chen X et al. (2007). Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem 282: 4702–4710.
Ding Y, Kim JK, Kim SI, Na HJ, Jun SY, Lee SJ et al. (2010). TGF-beta1 protects against mesangial cell apoptosis via induction of autophagy. J Biol Chem 285: 37909–37919.
Ding ZB, Shi YH, Zhou J, Qiu SJ, Xu Y, Dai Z et al. (2008). Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res 68: 9167–9175.
Djavaheri-Mergny M, Amelotti M, Mathieu J, Besancon F, Bauvy C, Souquere S et al. (2006). NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy. J Biol Chem 281: 30373–30382.
Donohue E, Tovey A, Vogl AW, Arns S, Sternberg E, Young RN et al. (2011). Inhibition of autophagosome formation by the benzoporphyrin derivative verteporfin. J Biol Chem 286: 7290–7300.
Eby KG, Rosenbluth JM, Mays DJ, Marshall CB, Barton CE, Sinha S et al. (2010). ISG20L1 is a p53 family target gene that modulates genotoxic stress-induced autophagy. Mol Cancer 9: 95.
Eccles DM, Russell SE, Haites NE, Atkinson R, Bell DW, Gruber L et al. (1992). Early loss of heterozygosity on 17q in ovarian cancer. The Abe Ovarian Cancer Genetics Group. Oncogene 7: 2069–2072.
Edinger AL, Cinalli RM, Thompson CB . (2003). Rab7 prevents growth factor-independent survival by inhibiting cell-autonomous nutrient transporter expression. Dev Cell 5: 571–582.
Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W et al. (2011). Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331: 456–461.
Elgendy M, Sheridan C, Brumatti G, Martin SJ . (2011). Oncogenic ras-induced expression of noxa and beclin-1 promotes autophagic cell death and limits clonogenic survival. Mol Cell 42: 23–35.
Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T et al. (2010). Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal 3: ra81.
Feng Z, Levine AJ . (2010). The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol 20: 427–434.
Fu L, Kim YA, Wang X, Wu X, Yue P, Lonial S et al. (2009). Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mTOR axis and induces autophagy. Cancer Res 69: 8967–8976.
Fujii S, Mitsunaga S, Yamazaki M, Hasebe T, Ishii G, Kojima M et al. (2008). Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome. Cancer Sci 99: 1813–1819.
Fujiwara K, Daido S, Yamamoto A, Kobayashi R, Yokoyama T, Aoki H et al. (2008). Pivotal role of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in apoptosis and autophagy. J Biol Chem 283: 388–397.
Fung C, Lock R, Gao S, Salas E, Debnath J . (2008). Induction of autophagy during extracellular matrix detachment promotes cell survival. Mol Biol Cell 19: 797–806.
Futreal PA, Soderkvist P, Marks JR, Iglehart JD, Cochran C, Barrett JC et al. (1992). Detection of frequent allelic loss on proximal chromosome 17q in sporadic breast carcinoma using microsatellite length polymorphisms. Cancer Res 52: 2624–2627.
Gajewska M, Gajkowska B, Motyl T . (2005). Apoptosis and autophagy induced by TGF-B1 in bovine mammary epithelial BME-UV1 cells. J Physiol Pharmacol 56 (Suppl 3): 143–157.
Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X . (2009). ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284: 12297–12305.
Gao P, Bauvy C, Souquere S, Tonelli G, Liu L, Zhu Y et al. (2010). The Bcl-2 homology domain 3 mimetic gossypol induces both Beclin 1-dependent and Beclin 1-independent cytoprotective autophagy in cancer cells. J Biol Chem 285: 25570–25781.
Gao W, Shen Z, Shang L, Wang X . (2011). Upregulation of human autophagy-initiation kinase ULK1 by tumor suppressor p53 contributes to DNA-damage-induced cell death. Cell Death Differ (doi:10.1038/cdd.2011.33).
Gao X, Zacharek A, Salkowski A, Grignon DJ, Sakr W, Porter AT et al. (1995). Loss of heterozygosity of the BRCA1 and other loci on chromosome 17q in human prostate cancer. Cancer Res 55: 1002–1005.
Ghavami S, Asoodeh A, Klonisch T, Halayko AJ, Kadkhoda K, Kroczak TJ et al. (2008). Brevinin-2R(1) semi-selectively kills cancer cells by a distinct mechanism, which involves the lysosomal-mitochondrial death pathway. J Cell Mol Med 12: 1005–1022.
Gu Y, Wang C, Cohen A . (2004). Effect of IGF-1 on the balance between autophagy of dysfunctional mitochondria and apoptosis. FEBS Lett 577: 357–360.
Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G et al. (2011). Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25: 460–470.
Gupta A, Roy S, Lazar AJ, Wang WL, McAuliffe JC, Reynoso D et al. (2010). Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc Natl Acad Sci USA 107: 14333–14338.
Gutierrez MG, Munafo DB, Beron W, Colombo MI . (2004). Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci 117: 2687–2697.
Han J, Hou W, Goldstein LA, Lu C, Stolz DB, Yin XM et al. (2008). Involvement of protective autophagy in TRAIL resistance of apoptosis-defective tumor cells. J Biol Chem 283: 19665–19677.
Han W, Li L, Qiu S, Lu Q, Pan Q, Gu Y et al. (2007). Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol Cancer Ther 6: 1641–1649.
Herrero-Martin G, Hoyer-Hansen M, Garcia-Garcia C, Fumarola C, Farkas T, Lopez-Rivas A et al. (2009). TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J 28: 677–685.
Hoyer-Hansen M, Jaattela M . (2007). AMP-activated protein kinase: a universal regulator of autophagy? Autophagy 3: 381–383.
Hsu KF, Wu CL, Huang SC, Wu CM, Hsiao JR, Yo YT et al. (2009). Cathepsin L mediates resveratrol-induced autophagy and apoptotic cell death in cervical cancer cells. Autophagy 5: 451–460.
Huang S, Sinicrope FA . (2010). Celecoxib-induced apoptosis is enhanced by ABT-737 and by inhibition of autophagy in human colorectal cancer cells. Autophagy 6: 256–269.
Huang X, Bai HM, Chen L, Li B, Lu YC . (2010). Reduced expression of LC3B-II and Beclin 1 in glioblastoma multiforme indicates a down-regulated autophagic capacity that relates to the progression of astrocytic tumors. J Clin Neurosci 17: 1515–1519.
Hwang J, Lee HJ, Lee WH, Suk K . (2010). NF-kappaB as a common signaling pathway in ganglioside-induced autophagic cell death and activation of astrocytes. J Neuroimmunol 226: 66–72.
Indelicato M, Pucci B, Schito L, Reali V, Aventaggiato M, Mazzarino MC et al. (2010). Role of hypoxia and autophagy in MDA-MB-231 invasiveness. J Cell Physiol 223: 359–368.
Iwamaru A, Kondo Y, Iwado E, Aoki H, Fujiwara K, Yokoyama T et al. (2007). Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells. Oncogene 26: 1840–1851.
Jager S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P et al. (2004). Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 117: 4837–4848.
Jiang H, Martin V, Alonso M, Gomez-Manzano C, Fueyo J . (2010b). RB-E2F1: molecular rheostat for autophagy and apoptosis. Autophagy 6: 1216–1217.
Jiang H, Martin V, Gomez-Manzano C, Johnson DG, Alonso M, White E et al. (2010a). The RB-E2F1 pathway regulates autophagy. Cancer Res 70: 7882–7893.
Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J et al. (2009). ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20: 1992–2003.
Kamitsuji Y, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E et al. (2008). The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ 15: 1712–1722.
Kandouz M, Haidara K, Zhao J, Brisson ML, Batist G . (2010). The EphB2 tumor suppressor induces autophagic cell death via concomitant activation of the ERK1/2 and PI3K pathways. Cell Cycle 9: 398–407.
Kang C, You YJ, Avery L . (2007). Dual roles of autophagy in the survival of Caenorhabditis elegans during starvation. Genes Dev 21: 2161–2171.
Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Kim SS et al. (2009). Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability. J Pathol 217: 702–706.
Karpathiou G, Sivridis E, Koukourakis M, Mikroulis D, Bouros D, Froudarakis M et al. (2010). LC3A autophagic activity and prognostic significance in non-small cell lung carcinomas. Chest (doi:10.1378/chest.10-1831).
Kashuba VI, Gizatullin RZ, Protopopov AI, Allikmets R, Korolev S, Li J et al. (1997). NotI linking/jumping clones of human chromosome 3: mapping of the TFRC, RAB7 and HAUSP genes to regions rearranged in leukemia and deleted in solid tumors. FEBS Lett 419: 181–185.
Kim EH, Sohn S, Kwon HJ, Kim SU, Kim MJ, Lee SJ et al. (2007). Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells. Cancer Res 67: 6314–6324.
Kim J, Kundu M, Viollet B, Guan KL . (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13: 132–141.
Kim KW, Hwang M, Moretti L, Jaboin JJ, Cha YI, Lu B . (2008b). Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer. Autophagy 4: 659–668.
Kim KW, Moretti L, Mitchell LR, Jung DK, Lu B . (2009b). Combined Bcl-2/mammalian target of rapamycin inhibition leads to enhanced radiosensitization via induction of apoptosis and autophagy in non-small cell lung tumor xenograft model. Clin Cancer Res 15: 6096–6105.
Kim MS, Jeong EG, Ahn CH, Kim SS, Lee SH, Yoo NJ . (2008a). Frameshift mutation of UVRAG, an autophagy-related gene, in gastric carcinomas with microsatellite instability. Hum Pathol 39: 1059–1063.
Kim RH, Coates JM, Bowles TL, McNerney GP, Sutcliffe J, Jung JU et al. (2009a). Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis. Cancer Res 69: 700–708.
Kiyono K, Suzuki HI, Matsuyama H, Morishita Y, Komuro A, Kano MR et al. (2009). Autophagy is activated by TGF-beta and potentiates TGF-beta-mediated growth inhibition in human hepatocellular carcinoma cells. Cancer Res 69: 8844–8852.
Koesters R, Kaissling B, Lehir M, Picard N, Theilig F, Gebhardt R et al. (2010). Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am J Pathol 177: 632–643.
Komata T, Kanzawa T, Takeuchi H, Germano IM, Schreiber M, Kondo Y et al. (2003). Antitumour effect of cyclin-dependent kinase inhibitors (p16(INK4A), p18(INK4C), p19(INK4D), p21(WAF1/CIP1) and p27(KIP1)) on malignant glioma cells. Br J Cancer 88: 1277–1280.
Koukourakis MI, Giatromanolaki A, Sivridis E, Pitiakoudis M, Gatter KC, Harris AL . (2010). Beclin 1 over- and underexpression in colorectal cancer: distinct patterns relate to prognosis and tumour hypoxia. Br J Cancer 103: 1209–1214.
Kuo HP, Lee DF, Chen CT, Liu M, Chou CK, Lee HJ et al. (2010). ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway. Sci Signal 3: ra9.
Laane E, Tamm KP, Buentke E, Ito K, Kharaziha P, Oscarsson J et al. (2009). Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy. Cell Death Differ 16: 1018–1029.
Lazova R, Klump V, Pawelek J . (2010). Autophagy in cutaneous malignant melanoma. J Cutan Pathol 37: 256–268.
Lazova R, Pawelek JM . (2009). Why do melanomas get so dark? Exp Dermatol 18: 934–938.
Levine B, Kroemer G . (2008). Autophagy in the pathogenesis of disease. Cell 132: 27–42.
Levine B, Mizushima N, Virgin HW . (2011). Autophagy in immunity and inflammation. Nature 469: 323–335.
Li BX, Li CY, Peng RQ, Wu XJ, Wang HY, Wan DS et al. (2009). The expression of beclin 1 is associated with favorable prognosis in stage IIIB colon cancers. Autophagy 5: 303–306.
Li X, Fan Z . (2010). The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex. Cancer Res 70: 5942–5952.
Li Z, Chen B, Wu Y, Jin F, Xia Y, Liu X . (2010). Genetic and epigenetic silencing of the beclin 1 gene in sporadic breast tumors. BMC Cancer 10: 98.
Lian J, Wu X, He F, Karnak D, Tang W, Meng Y et al. (2011). A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum. Cell Death Differ 18: 60–71.
Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M et al. (2007). The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9: 218–224.
Liu D, Huang Y, Chen B, Zeng J, Guo N, Zhang S et al. (2011). Activation of mammalian target of rapamycin pathway confers adverse outcome in nonsmall cell lung carcinoma. Cancer (doi:10.1002/cncr.25959).
Lock R, Roy S, Kenific CM, Su JS, Salas E, Ronen SM et al. (2011). Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell 22: 165–178.
Lorin S, Borges A, Ribeiro Dos Santos L, Souquere S, Pierron G, Ryan KM et al. (2009). c-Jun NH2-terminal kinase activation is essential for DRAM-dependent induction of autophagy and apoptosis in 2-methoxyestradiol-treated Ewing sarcoma cells. Cancer Res 69: 6924–6931.
Lorin S, Pierron G, Ryan KM, Codogno P, Djavaheri-Mergny M . (2010). Evidence for the interplay between JNK and p53-DRAM signalling pathways in the regulation of autophagy. Autophagy 6: 153–154.
Lovas A, Radke D, Albrecht D, Yilmaz ZB, Moller U, Habenicht AJ et al. (2008). Differential RelA- and RelB-dependent gene transcription in LTbetaR-stimulated mouse embryonic fibroblasts. BMC Genomics 9: 606.
Lu Z, Luo RZ, Lu Y, Zhang X, Yu Q, Khare S et al. (2008). The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest 118: 3917–3929.
Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T et al. (2005). Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120: 237–248.
Ma X, Piao S, Wang DW, McAfee QW, Nathanson KL, Lum JJ et al. (2011). Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma. Clin Cancer Res 17: 1–12.
Maddodi N, Huang W, Havighurst T, Kim K, Longley BJ, Setaluri V . (2010). Induction of autophagy and inhibition of melanoma growth in vitro and in vivo by hyperactivation of oncogenic BRAF. J Invest Dermatol 130: 1657–1667.
Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA et al. (2007a). BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy 3: 374–346.
Maiuri MC, Galluzzi L, Morselli E, Kepp O, Malik SA, Kroemer G . (2010). Autophagy regulation by p53. Curr Opin Cell Biol 22: 181–185.
Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P et al. (2007b). Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 26: 2527–2539.
Maiuri MC, Malik SA, Morselli E, Kepp O, Criollo A, Mouchel PL et al. (2009). Stimulation of autophagy by the p53 target gene Sestrin2. Cell Cycle 8: 1571–1576.
Marino G, Salvador-Montoliu N, Fueyo A, Knecht E, Mizushima N, Lopez-Otin C . (2007). Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J Biol Chem 282: 18573–18583.
Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K et al. (2007). Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 21: 1367–1381.
Mathieu V, Le Mercier M, De Neve N, Sauvage S, Gras T, Roland I et al. (2007). Galectin-1 knockdown increases sensitivity to temozolomide in a B16F10 mouse metastatic melanoma model. J Invest Dermatol 127: 2399–2410.
McPhee CK, Logan MA, Freeman MR, Baehrecke EH . (2010). Activation of autophagy during cell death requires the engulfment receptor Draper. Nature 465: 1093–1096.
Meschini S, Condello M, Calcabrini A, Marra M, Formisano G, Lista P et al. (2008). The plant alkaloid voacamine induces apoptosis-independent autophagic cell death on both sensitive and multidrug resistant human osteosarcoma cells. Autophagy 4: 1020–1033.
Miao Y, Zhang Y, Chen Y, Chen L, Wang F . (2010). GABARAP is overexpressed in colorectal carcinoma and correlates with shortened patient survival. Hepatogastroenterology 57: 257–261.
Miracco C, Cevenini G, Franchi A, Luzi P, Cosci E, Mourmouras V et al. (2010). Beclin 1 and LC3 autophagic gene expression in cutaneous melanocytic lesions. Hum Pathol 41: 503–512.
Miracco C, Cosci E, Oliveri G, Luzi P, Pacenti L, Monciatti I et al. (2007). Protein and mRNA expression of autophagy gene Beclin 1 in human brain tumours. Int J Oncol 30: 429–436.
Mizushima N, Levine B, Cuervo AM, Klionsky DJ . (2008). Autophagy fights disease through cellular self-digestion. Nature 451: 1069–1075.
Morselli E, Tasdemir E, Maiuri MC, Galluzzi L, Kepp O, Criollo A et al. (2008). Mutant p53 protein localized in the cytoplasm inhibits autophagy. Cell Cycle 7: 3056–3061.
Narita M, Young AR . (2009). Autophagy facilitates oncogene-induced senescence. Autophagy 5: 1046–1047.
Negri T, Tarantino E, Orsenigo M, Reid JF, Gariboldi M, Zambetti M et al. (2010). Chromosome band 17q21 in breast cancer: significant association between beclin 1 loss and HER2/NEU amplification. Genes Chromosomes Cancer 49: 901–909.
Nishida Y, Arakawa S, Fujitani K, Yamaguchi H, Mizuta T, Kanaseki T et al. (2009). Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461: 654–658.
Nivon M, Richet E, Codogno P, Arrigo AP, Kretz-Remy C . (2009). Autophagy activation by NFkappaB is essential for cell survival after heat shock. Autophagy 5: 766–783.
Noble CG, Dong JM, Manser E, Song H . (2008). Bcl-xL and UVRAG cause a monomer-dimer switch in Beclin1. J Biol Chem 283: 26274–26282.
Nomura H, Uzawa K, Yamano Y, Fushimi K, Ishigami T, Kouzu Y et al. (2009). Overexpression and altered subcellular localization of autophagy-related 16-like 1 in human oral squamous-cell carcinoma: correlation with lymphovascular invasion and lymph-node metastasis. Hum Pathol 40: 83–91.
O'Donovan TR, O'Sullivan GC, McKenna S . (2011). Induction of autophagy by drug-resistant esophageal cancer cells promotes their survival and recovery following treatment with chemotherapeutics. Autophagy 7: 509–524.
Ostenfeld MS, Hoyer-Hansen M, Bastholm L, Fehrenbacher N, Olsen OD, Groth-Pedersen L et al. (2008). Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation. Autophagy 4: 487–499.
Othman EQ, Kaur G, Mutee AF, Muhammad TS, Tan ML . (2009). Immunohistochemical expression of MAP1LC3A and MAP1LC3B protein in breast carcinoma tissues. J Clin Lab Anal 23: 249–258.
Paglin S, Lee NY, Nakar C, Fitzgerald M, Plotkin J, Deuel B et al. (2005). Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res 65: 11061–11070.
Pankiv S, Alemu EA, Brech A, Bruun JA, Lamark T, Overvatn A et al. (2010). FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport. J Cell Biol 188: 253–269.
Pankiv S, Johansen T . (2010). FYCO1: linking autophagosomes to microtubule plus end-directing molecular motors. Autophagy 6: 550–552.
Park MA, Yacoub A, Rahmani M, Zhang G, Hart L, Hagan MP et al. (2008). OSU-03012 stimulates PKR-like endoplasmic reticulum-dependent increases in 70-kDa heat shock protein expression, attenuating its lethal actions in transformed cells. Mol Pharmacol 73: 1168–1184.
Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N et al. (2005). Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122: 927–939.
Pirtoli L, Cevenini G, Tini P, Vannini M, Oliveri G, Marsili S et al. (2009). The prognostic role of Beclin 1 protein expression in high-grade gliomas. Autophagy 5: 930–936.
Platt FM, Hurst CD, Taylor CF, Gregory WM, Harnden P, Knowles MA . (2009). Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res 15: 6008–6017.
Polager S, Ofir M, Ginsberg D . (2008). E2F1 regulates autophagy and the transcription of autophagy genes. Oncogene 27: 4860–4864.
Portillo JA, Okenka G, Reed E, Subauste A, Van Grol J, Gentil K et al. (2010). The CD40-autophagy pathway is needed for host protection despite IFN-Gamma-dependent immunity and CD40 induces autophagy via control of P21 levels. PLoS One 5: e14472.
Qadir MA, Kwok B, Dragowska WH, To KH, Le D, Bally MB et al. (2008). Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Res Treat 112: 389–403.
Reef S, Kimchi A . (2008). Nucleolar p19ARF, unlike mitochondrial smARF, is incapable of inducing p53-independent autophagy. Autophagy 4: 866–869.
Reef S, Shifman O, Oren M, Kimchi A . (2007). The autophagic inducer smARF interacts with and is stabilized by the mitochondrial p32 protein. Oncogene 26: 6677–6683.
Reef S, Zalckvar E, Shifman O, Bialik S, Sabanay H, Oren M et al. (2006). A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death. Mol Cell 22: 463–475.
Roca H, Varsos Z, Pienta KJ . (2008). CCL2 protects prostate cancer PC3 cells from autophagic death via phosphatidylinositol 3-kinase/AKT-dependent survivin up-regulation. J Biol Chem 283: 25057–25073.
Russell SE, Hickey GI, Lowry WS, White P, Atkinson RJ . (1990). Allele loss from chromosome 17 in ovarian cancer. Oncogene 5: 1581–1583.
Saito H, Inazawa J, Saito S, Kasumi F, Koi S, Sagae S et al. (1993). Detailed deletion mapping of chromosome 17q in ovarian and breast cancers: 2-cM region on 17q21.3 often and commonly deleted in tumors. Cancer Res 53: 3382–3385.
Sanchez-Cespedes M . (2007). A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome. Oncogene 26: 7825–7832.
Scarlatti F, Maffei R, Beau I, Codogno P, Ghidoni R . (2008). Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells. Cell Death Differ 15: 1318–1329.
Scherz-Shouval R, Weidberg H, Gonen C, Wilder S, Elazar Z, Oren M . (2010). p53-dependent regulation of autophagy protein LC3 supports cancer cell survival under prolonged starvation. Proc Natl Acad Sci USA 107: 18511–18516.
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW . (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593–602.
Shingu T, Fujiwara K, Bogler O, Akiyama Y, Moritake K, Shinojima N et al. (2009). Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells. Int J Cancer 124: 1060–1071.
Sivridis E, Koukourakis MI, Zois CE, Ledaki I, Ferguson DJ, Harris AL et al. (2010). LC3A-positive light microscopy detected patterns of autophagy and prognosis in operable breast carcinomas. Am J Pathol 176: 2477–2489.
Steffan JJ, Cardelli JA . (2010). Thiazolidinediones induce Rab7-RILP-MAPK-dependent juxtanuclear lysosome aggregation and reduce tumor cell invasion. Traffic 11: 274–286.
Steffan JJ, Williams BC, Welbourne T, Cardelli JA . (2010). HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na+-H+ exchangers. J Cell Sci 123: 1151–1159.
Stenmark H . (2010). The Sir Hans Krebs Lecture. How a lipid mediates tumour suppression. Delivered on 29 June 2010 at the 35th FEBS Congress in Gothenburg, Sweden. FEBS J 277: 4837–4848.
Suzuki HI, Kiyono K, Miyazono K . (2010). Regulation of autophagy by transforming growth factor-beta (TGFbeta) signaling. Autophagy 6: 645–647.
Tangir J, Muto MG, Berkowitz RS, Welch WR, Bell DA, Mok SC . (1996). A 400 kb novel deletion unit centromeric to the BRCA1 gene in sporadic epithelial ovarian cancer. Oncogene 12: 735–740.
Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D'Amelio M et al. (2008). Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 10: 676–687.
Tormo D, Checinska A, Alonso-Curbelo D, Perez-Guijarro E, Canon E, Riveiro-Falkenbach E et al. (2009). Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells. Cancer Cell 16: 103–114.
Totoki Y, Tatsuno K, Yamamoto S, Arai Y, Hosoda F, Ishikawa S et al. (2011). High-resolution characterization of a hepatocellular carcinoma genome. Nat Genet 43: 464–469.
Turcotte S, Chan DA, Sutphin PD, Hay MP, Denny WA, Giaccia AJ . (2008). A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 14: 90–102.
Ueno T, Sato W, Horie Y, Komatsu M, Tanida I, Yoshida M et al. (2008). Loss of Pten, a tumor suppressor, causes the strong inhibition of autophagy without affecting LC3 lipidation. Autophagy 4: 692–700.
Voss V, Senft C, Lang V, Ronellenfitsch MW, Steinbach JP, Seifert V et al. (2010). The pan-Bcl-2 inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma. Mol Cancer Res 8: 1002–1016.
Wan XB, Fan XJ, Chen MY, Xiang J, Huang PY, Guo L et al. (2010). Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy 6: 395–404.
Wang J, Whiteman MW, Lian H, Wang G, Singh A, Huang D et al. (2009). A non-canonical MEK/ERK signaling pathway regulates autophagy via regulating Beclin 1. J Biol Chem 284: 21412–21424.
Wild P, Dikic I . (2010). Mitochondria get a Parkin’ ticket. Nat Cell Biol 12: 104–106.
Wu WK, Cho CH, Lee CW, Wu K, Fan D, Yu J et al. (2010a). Proteasome inhibition: a new therapeutic strategy to cancer treatment. Cancer Lett 293: 15–22.
Wu WK, Cho CH, Lee CW, Wu YC, Yu L, Li ZJ et al. (2010c). Macroautophagy and ERK phosphorylation counteract the antiproliferative effect of proteasome inhibitor in gastric cancer cells. Autophagy 6: 228–238.
Wu WK, Sakamoto KM, Milani M, Aldana-Masankgay G, Fan D, Wu K et al. (2010b). Macroautophagy modulates cellular response to proteasome inhibitors in cancer therapy. Drug Resist Updat 13: 87–92.
Xu DZ, Geng QR, Tian Y, Cai MY, Fang XJ, Zhan YQ et al. (2010). Activated mammalian target of rapamycin is a potential therapeutic target in gastric cancer. BMC Cancer 10: 536.
Yacoub A, Hamed HA, Allegood J, Mitchell C, Spiegel S, Lesniak MS et al. (2010). PERK-dependent regulation of ceramide synthase 6 and thioredoxin play a key role in mda-7/IL-24-induced killing of primary human glioblastoma multiforme cells. Cancer Res 70: 1120–1129.
Yang PM, Liu YL, Lin YC, Shun CT, Wu MS, Chen CC . (2010). Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res 70: 7699–7709.
Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H et al. (2011). Pancreatic cancers require autophagy for tumor growth. Genes Dev 25: 717–729.
Yang Z, Klionsky DJ . (2010). Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22: 124–131.
Yaswen P, Campisi J . (2007). Oncogene-induced senescence pathways weave an intricate tapestry. Cell 128: 233–234.
Yee KS, Wilkinson S, James J, Ryan KM, Vousden KH . (2009). PUMA- and Bax-induced autophagy contributes to apoptosis. Cell Death Differ 16: 1135–1145.
Yoshioka A, Miyata H, Doki Y, Yamasaki M, Sohma I, Gotoh K et al. (2008). LC3, an autophagosome marker, is highly expressed in gastrointestinal cancers. Int J Oncol 33: 461–468.
Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF et al. (2009). Autophagy mediates the mitotic senescence transition. Genes Dev 23: 798–803.
Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L et al. (2006). Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 8: 1124–1132.
Yue Z, Jin S, Yang C, Levine AJ, Heintz N . (2003). Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 100: 15077–15082.
Zeng X, Kinsella TJ . (2008). Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Cancer Res 68: 2384–2390.
Zhang L, Yu J, Pan H, Hu P, Hao Y, Cai W et al. (2007). Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci USA 104: 19023–19028.
Zhang YJ, Dai Q, Sun DF, Xiong H, Tian XQ, Gao FH et al. (2009b). mTOR signaling pathway is a target for the treatment of colorectal cancer. Ann Surg Oncol 16: 2617–2628.
Zhang Z, Shao Z, Xiong L, Che B, Deng C, Xu W . (2009a). Expression of Beclin1 in osteosarcoma and the effects of down-regulation of autophagy on the chemotherapeutic sensitivity. J Huazhong Univ Sci Technolog Med Sci 29: 737–740.
Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S et al. (2010). Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol 12: 665–675.
Zhou F, Yang Y, Xing D . (2011). Bcl-2 and Bcl-xL play important roles in the crosstalk between autophagy and apoptosis. FEBS J 278: 403–413.
This work was supported by research grant from the CUHK Group Research Scheme (3110043) and CUHK Focused Investments Scheme-Scheme C.
The authors declare no conflict of interest.
About this article
Cite this article
Wu, W., Coffelt, S., Cho, C. et al. The autophagic paradox in cancer therapy. Oncogene 31, 939–953 (2012). https://doi.org/10.1038/onc.2011.295
- cell survival
- cell death
miR-29c-3p inhibits autophagy and cisplatin resistance in ovarian cancer by regulating FOXP1/ATG14 pathway
Cell Cycle (2020)
Scientific Reports (2020)
Molecular Cancer (2020)
Journal of Experimental & Clinical Cancer Research (2019)
Can Hinokitiol Kill Cancer Cells? Alternative Therapeutic Anticancer Agent via Autophagy and Apoptosis
The Korean Journal of Clinical Laboratory Science (2019)