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Autophagy as a target for anticancer therapy

Abstract

Autophagy is an important homeostatic cellular recycling mechanism responsible for degrading unnecessary or dysfunctional cellular organelles and proteins in all living cells. Autophagy is particularly active during metabolic stress. In the cancer cell it fulfils a dual role, having tumor-promoting and tumor-suppressing properties. Functional autophagy prevents necrosis and inflammation, which can lead to genetic instability. On the other hand, autophagy might be important for tumor progression by providing energy through its recycling mechanism during unfavorable metabolic circumstances. A central checkpoint that negatively regulates autophagy is mTOR, and anticancer drugs inhibiting the PI3K/Akt/mTOR axis putatively stimulate autophagy. However, whether autophagy contributes to the antitumor effect of these drugs or to drug resistance is largely unknown. The antimalarial drugs chloroquine and hydroxychloroquine inhibit autophagy, leading to increased cytotoxicity in combination with several anticancer drugs in preclinical models. The therapeutic clinical roles of autophagy induction and inhibition remain to be defined. To improve our understanding of autophagy in human cancers new methods for measuring autophagy in clinical samples need to be developed. This Review delineates the possible role of autophagy as a novel target for anticancer therapy.

Key Points

  • Autophagy is a homeostatic cellular recycling mechanism that mediates removal of old or dysfunctional proteins and organelles, and is particularly important for cell survival during conditions of metabolic stress

  • Autophagy might have a dual role in cancer: it can allow cancer cells to overcome metabolic stress (hypoxia, lack of nutrients) or suppress tumor progression through degradation of oncogenic proteins

  • Autophagy is controlled by the Atg family of proteins and can be divided into several distinct phases; mTORC1 is a key regulator of autophagy signaling

  • Many anticancer drugs (such as inhibitors of mTORC1, the proteasome, or histone deacetylases) induce autophagy; whether autophagy enhances their antitumor properties or contributes to therapeutic resistance often remains unclear

  • Autophagy inhibitors such as chloroquine and hydroxychloroquine showed efficacy in combination with other anticancer drugs in preclinical models, and clinical studies are underway

  • Being a dynamic process, autophagy is difficult to measure; current detection approaches include electron microscopy and immunohistochemical methods, but the 'optimal' technique for clinical application remains to be discovered

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Figure 1: Regulation of autophagy.
Figure 2: Autophagy cascade.

References

  1. 1

    Mizushima, N. Autophagy: process and function. Genes Dev. 21, 2861–2873 (2007).

    CAS  Google Scholar 

  2. 2

    Levine, B. & Klionsky, D. J. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 6, 463–477 (2004).

    CAS  PubMed  Google Scholar 

  3. 3

    Uttenweiler, A. & Mayer, A. Microautophagy in the yeast Saccharomyces cerevisiae . Methods Mol. Biol. 445, 245–259 (2008).

    CAS  PubMed  Google Scholar 

  4. 4

    Arias, E. & Cuervo, A. M. Chaperone-mediated autophagy in protein quality control. Curr. Opin. Cell Biol. 23, 184–189 (2011).

    CAS  PubMed  Google Scholar 

  5. 5

    Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Levine, B. Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 120, 159–162 (2005).

    CAS  PubMed  Google Scholar 

  7. 7

    Yang, Z. & Klionsky, D. J. Eaten alive: a history of macroautophagy. Nat. Cell Biol. 12, 814–822 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Korolchuk, V. I., Mansilla, A., Menzies, F. M. & Rubinsztein, D. C. Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol. Cell 33, 517–527 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Degenhardt, K. et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10, 51–64 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Apel, A., Herr, I., Schwarz, H., Rodemann, H. P. & Mayer, A. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res. 68, 1485–1494 (2008).

    CAS  PubMed  Google Scholar 

  11. 11

    Katayama, M., Kawaguchi, T., Berger, M. S. & Pieper, R. O. DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death Differ. 14, 548–558 (2007).

    CAS  PubMed  Google Scholar 

  12. 12

    Qadir, M. A. et al. Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Res. Treat. 112, 389–403 (2008).

    CAS  PubMed  Google Scholar 

  13. 13

    Vazquez-Martin, A., Oliveras-Ferraros, C. & Menendez, J. A. Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab. PLoS ONE 4, e6251 (2009).

    PubMed  PubMed Central  Google Scholar 

  14. 14

    Carew, J. S. et al. Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation. J. Cell. Mol. Med. 14, 2448–2459 (2010).

    CAS  PubMed  Google Scholar 

  15. 15

    Baehrecke, E. H. Autophagy: dual roles in life and death? Nat. Rev. Mol. Cell Biol. 6, 505–510 (2005).

    CAS  PubMed  Google Scholar 

  16. 16

    Kim, K. W. et al. Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer. Autophagy 4, 659–668 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Kim, K. W., Moretti, L., Mitchell, L. R., Jung, D. K. & Lu, B. 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 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Tormo, D. et al. Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells. Cancer Cell 16, 103–114 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Weihua, Z. et al. Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell 13, 385–393 (2008).

    PubMed  PubMed Central  Google Scholar 

  20. 20

    Levine, B. & Yuan, J. Autophagy in cell death: an innocent convict? J. Clin. Invest. 115, 2679–2688 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 127, 5–19 (2006).

    Google Scholar 

  22. 22

    Kamada, Y. et al. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J. Cell Biol. 150, 1507–1513 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Chang, Y. Y. & Neufeld, T. P. An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation. Mol. Biol. Cell 20, 2004–2014 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Yang, Z. & Klionsky, D. J. Mammalian autophagy: core molecular machinery and signaling regulation. Curr. Opin. Cell Biol. 22, 124–131 (2010).

    CAS  PubMed  Google Scholar 

  25. 25

    He, C. K. & Klionsky, D. J. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43, 67–93 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527–532 (1994).

    CAS  Google Scholar 

  27. 27

    Manning, B. D. et al. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev. 19, 1773–1778 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Sun, S. Y. et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 65, 7052–7058 (2005).

    CAS  PubMed  Google Scholar 

  29. 29

    Nicklin, P. et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521–534 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Shinojima, N., Yokoyama, T., Kondo, Y. & Kondo, S. Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy 3, 635–637 (2007).

    CAS  PubMed  Google Scholar 

  31. 31

    Wong, C. H. et al. Simultaneous induction of non-canonical autophagy and apoptosis in cancer cells by ROS-dependent ERK and JNK activation. PLoS One 5, e9996 (2010).

    PubMed  PubMed Central  Google Scholar 

  32. 32

    Xie, Z. & Klionsky, D. J. Autophagosome formation: core machinery and adaptations. Nat. Cell Biol. 9, 1102–1109 (2007).

    CAS  PubMed  Google Scholar 

  33. 33

    Hayashi-Nishino, M. et al. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 11, 1433–1437 (2009).

    CAS  Google Scholar 

  34. 34

    Nishida, Y. et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461, 654–658 (2009).

    CAS  Google Scholar 

  35. 35

    Hailey, D. W. et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141, 656–667 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Ravikumar, B., Moreau, K., Jahreiss, L., Puri, C. & Rubinsztein, D. C. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat. Cell Biol. 12, 747–757 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Behrends, C., Sowa, M. E., Gygi, S. P. & Harper, J. W. Network organization of the human autophagy system. Nature 466, 68–76 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Young, A. R. et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 23, 798–803 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Jung, C. H. et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992–2003 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Lee, S. B. et al. ATG1, an autophagy regulator, inhibits cell growth by negatively regulating S6 kinase. EMBO Rep. 8, 360–365 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Kundu, M. et al. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 112, 1493–1502 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Fimia, G. M. et al. Ambra1 regulates autophagy and development of the nervous system. Nature 447, 1121–1125 (2007).

    CAS  PubMed  Google Scholar 

  44. 44

    Kihara, A., Noda, T., Ishihara, N. & Ohsumi, Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae . J. Cell Biol. 152, 519–530 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Itakura, E., Kishi, C., Inoue, K. & Mizushima, N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol. Biol. Cell 19, 5360–5372 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Sun, Q. et al. Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc. Natl Acad. Sci. USA 105, 19211–19216 (2008).

    CAS  Google Scholar 

  47. 47

    Zhong, Y. et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat. Cell Biol. 11, 468–476 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Takahashi, Y. et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat. Cell Biol. 9, 1142–1151 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Backer, J. M. The regulation and function of class III PI3Ks: novel roles for Vps34. Biochem. J. 410, 1–17 (2008).

    CAS  Google Scholar 

  50. 50

    Matsunaga, K. et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat. Cell Biol. 11, 385–396 (2009).

    CAS  Google Scholar 

  51. 51

    Young, A. R. et al. Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J. Cell Sci. 119, 3888–3900 (2006).

    CAS  PubMed  Google Scholar 

  52. 52

    Yen, W. L., Legakis, J. E., Nair, U. & Klionsky, D. J. Atg27 is required for autophagy-dependent cycling of Atg9. Mol. Biol. Cell 18, 581–593 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Legakis, J. E., Yen, W. L. & Klionsky, D. J. A cycling protein complex required for selective autophagy. Autophagy 3, 422–432 (2007).

    CAS  PubMed  Google Scholar 

  54. 54

    Tucker, K. A., Reggiori, F., Dunn, W. A., Jr & Klionsky, D. J. Atg23 is essential for the cytoplasm to vacuole targeting pathway and efficient autophagy but not pexophagy. J. Biol. Chem. 278, 48445–48452 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Reggiori, F., Tucker, K. A., Stromhaug, P. E. & Klionsky, D. J. The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure. Dev. Cell 6, 79–90 (2004).

    CAS  PubMed  Google Scholar 

  56. 56

    Ropolo, A. et al. The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells. J. Biol. Chem. 282, 37124–37133 (2007).

    CAS  PubMed  Google Scholar 

  57. 57

    Axe, E. L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685–701 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Yla-Anttila, P., Vihinen, H., Jokitalo, E. & Eskelinen, E. L. 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5, 1180–1185 (2009).

    Google Scholar 

  59. 59

    Tooze, S. A. & Yoshimori, T. The origin of the autophagosomal membrane. Nat. Cell Biol. 12, 831–835 (2010).

    CAS  PubMed  Google Scholar 

  60. 60

    Pankiv, S. et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131–24145 (2007).

    CAS  PubMed  Google Scholar 

  61. 61

    Schweers, R. L. et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc. Natl Acad. Sci. USA 104, 19500–19505 (2007).

    CAS  PubMed  Google Scholar 

  62. 62

    Amaravadi, R. K. et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin. Cancer Res. 17, 654–666 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Jager, S. et al. Role for Rab7 in maturation of late autophagic vacuoles. J. Cell Sci. 117, 4837–4848 (2004).

    PubMed  Google Scholar 

  64. 64

    Tanaka, Y. et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406, 902–906 (2000).

    CAS  Google Scholar 

  65. 65

    Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus . Science 306, 1037–1040 (2004).

    CAS  Google Scholar 

  66. 66

    Kuma, A. & Mizushima, N. Physiological role of autophagy as an intracellular recycling system: with an emphasis on nutrient metabolism. Semin. Cell Dev. Biol. 21, 683–690 (2010).

    CAS  PubMed  Google Scholar 

  67. 67

    White, E. & DiPaola, R. S. The double-edged sword of autophagy modulation in cancer. Clin. Cancer Res. 15, 5308–5316 (2009).

    PubMed  PubMed Central  Google Scholar 

  68. 68

    Mathew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer. Nat. Rev. Cancer 7, 961–967 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Harris, A. L. Hypoxia—a key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38–47 (2002).

    CAS  PubMed  Google Scholar 

  71. 71

    Chau, B. N. & Wang, J. Y. Coordinated regulation of life and death by RB. Nat. Rev. Cancer 3, 130–138 (2003).

    CAS  PubMed  Google Scholar 

  72. 72

    Lum, J. J. et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237–248 (2005).

    CAS  Google Scholar 

  73. 73

    Jin, S., DiPaola, R. S., Mathew, R. & White, E. Metabolic catastrophe as a means to cancer cell death. J. Cell Sci. 120, 379–383 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Liu, P., Cheng, H., Roberts, T. M. & Zhao, J. J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8, 627–644 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer 9, 550–562 (2009).

    CAS  PubMed  Google Scholar 

  76. 76

    Jin, S. & White, E. Role of autophagy in cancer: management of metabolic stress. Autophagy 3, 28–31 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Jin, S. & White, E. Tumor suppression by autophagy through the management of metabolic stress. Autophagy 4, 563–566 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Maclean, K. H., Dorsey, F. C., Cleveland, J. L. & Kastan, M. B. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J. Clin. Invest. 118, 79–88 (2008).

    CAS  PubMed  Google Scholar 

  79. 79

    Karantza-Wadsworth, V. et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 21, 1621–1635 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).

    CAS  PubMed  Google Scholar 

  82. 82

    Qu, X. et al. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128, 931–946 (2007).

    CAS  Google Scholar 

  83. 83

    Mathew, R. et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 137, 1062–1075 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Kongara, S. et al. Autophagy regulates keratin 8 homeostasis in mammary epithelial cells and in breast tumors. Mol. Cancer Res. 8, 873–884 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Rubinsztein, D. C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780–786 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Li, B. X. et al. The expression of beclin 1 is associated with favorable prognosis in stage IIIB colon cancers. Autophagy 5, 303–306 (2009).

    PubMed  Google Scholar 

  87. 87

    Chen, Y., Lu, Y., Lu, C. & Zhang, L. Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-1α expression. Pathol. Oncol. Res. 15, 487–493 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Martin, A. P. et al. Inhibition of MCL-1 enhances lapatinib toxicity and overcomes lapatinib resistance via BAK-dependent autophagy. Cancer Biol. Ther. 8, 2084–2096 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Pirtoli, L. et al. The prognostic role of Beclin 1 protein expression in high-grade gliomas. Autophagy 5, 930–936 (2009).

    PubMed  Google Scholar 

  90. 90

    Ding, Z. B. et al. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res. 68, 9167–9175 (2008).

    CAS  PubMed  Google Scholar 

  91. 91

    Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005).

    CAS  Google Scholar 

  92. 92

    Won, K. Y., Kim, G. Y., Kim, Y. W., Song, J. Y. & Lim, S. J. Clinicopathologic correlation of beclin-1 and bcl-2 expression in human breast cancer. Hum. Pathol. 41, 107–112 (2009).

    PubMed  Google Scholar 

  93. 93

    Ahn, C. H. et al. Expression of beclin-1, an autophagy-related protein, in gastric and colorectal cancers. APMIS 115, 1344–1349 (2007).

    PubMed  Google Scholar 

  94. 94

    Wan, X. B. et al. Elevated Beclin 1 expression is correlated with HIF-1α in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy 6, 395–404 (2010).

    CAS  PubMed  Google Scholar 

  95. 95

    Bellot, G. et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol. Cell Biol. 29, 2570–2581 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Band, M., Joel, A., Hernandez, A. & Avivi, A. Hypoxia-induced BNIP3 expression and mitophagy: in vivo comparison of the rat and the hypoxia-tolerant mole rat, Spalax ehrenbergi . FASEB J. 23, 2327–2335 (2009).

    CAS  PubMed  Google Scholar 

  97. 97

    Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Park, J. et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441, 1157–1161 (2006).

    CAS  PubMed  Google Scholar 

  99. 99

    Cesari, R. et al. Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc. Natl Acad. Sci. USA 100, 5956–5961 (2003).

    CAS  PubMed  Google Scholar 

  100. 100

    Poulogiannis, G. et al. PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice. Proc. Natl Acad. Sci. USA 107, 15145–15150 (2010).

    CAS  PubMed  Google Scholar 

  101. 101

    DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D. & Ellisen, L. W. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 22, 239–251 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Glick, D., Barth, S. & Macleod, K. F. Autophagy: cellular and molecular mechanisms. J. Pathol. 221, 3–12 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Lazova, R., Klump, V. & Pawelek, J. Autophagy in cutaneous malignant melanoma. J. Cutan. Pathol. 37, 256–268 (2009).

    PubMed  Google Scholar 

  104. 104

    Yoshioka, A. et al. LC3, an autophagosome marker, is highly expressed in gastrointestinal cancers. Int. J. Oncol. 33, 461–468 (2008).

    CAS  PubMed  Google Scholar 

  105. 105

    Cao, C. et al. Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res. 66, 10040–10047 (2006).

    CAS  PubMed  Google Scholar 

  106. 106

    Alonso, M. M. et al. Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death. Mol. Ther. 16, 487–493 (2008).

    CAS  PubMed  Google Scholar 

  107. 107

    Takeuchi, H. et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res. 65, 3336–3346 (2005).

    CAS  PubMed  Google Scholar 

  108. 108

    Paglin, S. et al. Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res. 65, 11061–11070 (2005).

    CAS  PubMed  Google Scholar 

  109. 109

    Yazbeck, V. Y. et al. Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma. Exp. Hematol. 36, 443–450 (2008).

    CAS  PubMed  Google Scholar 

  110. 110

    Crazzolara, R., Bradstock, K. F. & Bendall, L. J. RAD001 (Everolimus) induces autophagy in acute lymphoblastic leukemia. Autophagy 5, 727–728 (2009).

    CAS  PubMed  Google Scholar 

  111. 111

    Alvero, A. B. et al. NV-128, a novel isoflavone derivative, induces caspase-independent cell death through the Akt/mammalian target of rapamycin pathway. Cancer 115, 3204–3216 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Adams, J. The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5, 417–421 (2004).

    CAS  PubMed  Google Scholar 

  113. 113

    Ding, W. X. et al. Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. Mol. Cancer Ther. 8, 2036–2045 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Zhu, K., Dunner, K. Jr & McConkey, D. J. Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells. Oncogene 29, 451–462 (2010).

    CAS  PubMed  Google Scholar 

  115. 115

    Pandey, U. B. et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447, 859–863 (2007).

    CAS  PubMed  Google Scholar 

  116. 116

    Ertmer, A. et al. The anticancer drug imatinib induces cellular autophagy. Leukemia 21, 936–942 (2007).

    CAS  PubMed  Google Scholar 

  117. 117

    Basciani, S. et al. Imatinib interferes with survival of multi drug resistant Kaposi's sarcoma cells. FEBS Lett. 581, 5897–5903 (2007).

    CAS  PubMed  Google Scholar 

  118. 118

    Bilir, A. et al. Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma. Int. J. Oncol. 32, 829–839 (2008).

    CAS  PubMed  Google Scholar 

  119. 119

    Gupta, A. et al. Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc. Natl Acad. Sci. USA 107, 14333–14338 (2010).

    CAS  PubMed  Google Scholar 

  120. 120

    Milano, V., Piao, Y., LaFortune, T. & de Groot, J. Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. Mol. Cancer Ther. 8, 394–406 (2009).

    CAS  PubMed  Google Scholar 

  121. 121

    Bellodi, C. et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J. Clin. Invest. 119, 1109–1123 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Mishima, Y. et al. Autophagy and autophagic cell death are next targets for elimination of the resistance to tyrosine kinase inhibitors. Cancer Sci. 99, 2200–2208 (2008).

    CAS  PubMed  Google Scholar 

  123. 123

    Martin, A. P. et al. BCL-2 family inhibitors enhance histone deacetylase inhibitor and sorafenib lethality via autophagy and overcome blockade of the extrinsic pathway to facilitate killing. Mol. Pharmacol. 76, 327–341 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Shao, Y., Gao, Z., Marks, P. A. & Jiang, X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc. Natl Acad. Sci. USA 101, 18030–18035 (2004).

    CAS  PubMed  Google Scholar 

  125. 125

    Yamamoto, S. et al. Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-associated cell death in chondrosarcoma cell lines. Anticancer Res. 28, 1585–1591 (2008).

    CAS  PubMed  Google Scholar 

  126. 126

    Ellis, L. et al. The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy. Blood 114, 380–393 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Turzanski, J., Daniels, I. & Haynes, A. P. Involvement of macroautophagy in the caspase-independent killing of Burkitt lymphoma cell lines by rituximab. Br. J. Haematol. 145, 137–140 (2009).

    CAS  PubMed  Google Scholar 

  128. 128

    Giannopoulou, E., Antonacopoulou, A., Matsouka, P. & Kalofonos, H. P. Autophagy: novel action of panitumumab in colon cancer. Anticancer Res. 29, 5077–5082 (2009).

    CAS  PubMed  Google Scholar 

  129. 129

    Bursch, W. et al. Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis 17, 1595–1607 (1996).

    CAS  Google Scholar 

  130. 130

    Samaddar, J. S. et al. A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance. Mol. Cancer Ther. 7, 2977–2987 (2008).

    CAS  PubMed  Google Scholar 

  131. 131

    Pan, J. & Yeung, S. C. Recent advances in understanding the antineoplastic mechanisms of farnesyltransferase inhibitors. Cancer Res. 65, 9109–9112 (2005).

    CAS  PubMed  Google Scholar 

  132. 132

    Pan, J. et al. Autophagy induced by farnesyltransferase inhibitors in cancer cells. Cancer Biol. Ther. 7, 1679–1684 (2008).

    CAS  PubMed  Google Scholar 

  133. 133

    Albert, J. M. et al. Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin. Cancer Res. 13, 3033–3042 (2007).

    CAS  PubMed  Google Scholar 

  134. 134

    Munoz-Gamez, J. A. et al. PARP-1 is involved in autophagy induced by DNA damage. Autophagy 5, 61–74 (2009).

    CAS  PubMed  Google Scholar 

  135. 135

    Hoyer-Hansen, M., Bastholm, L., Mathiasen, I. S., Elling, F. & Jaattela, M. Vitamin D analog EB1089 triggers dramatic lysosomal changes and Beclin 1-mediated autophagic cell death. Cell Death Differ. 12, 1297–1309 (2005).

    CAS  PubMed  Google Scholar 

  136. 136

    Demasters, G., Di, X., Newsham, I., Shiu, R. & Gewirtz, D. A. Potentiation of radiation sensitivity in breast tumor cells by the vitamin D3 analogue, EB 1089, through promotion of autophagy and interference with proliferative recovery. Mol. Cancer Ther. 5, 2786–2797 (2006).

    CAS  PubMed  Google Scholar 

  137. 137

    Hoyer-Hansen, M. et al. Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol. Cell 25, 193–205 (2007).

    PubMed  Google Scholar 

  138. 138

    Kanzawa, T., Kondo, Y., Ito, H., Kondo, S. & Germano, I. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res. 63, 2103–2108 (2003).

    CAS  PubMed  Google Scholar 

  139. 139

    Kanzawa, T. et al. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene 24, 980–991 (2005).

    CAS  PubMed  Google Scholar 

  140. 140

    Qian, W., Liu, J., Jin, J., Ni, W. & Xu, W. Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1. Leuk. Res. 31, 329–339 (2007).

    PubMed  Google Scholar 

  141. 141

    Scarlatti, F. et al. Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling. FASEB J. 17, 2339–2341 (2003).

    CAS  PubMed  Google Scholar 

  142. 142

    Scarlatti, F., Maffei, R., Beau, I., Codogno, P. & Ghidoni, R. 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 (2008).

    CAS  PubMed  Google Scholar 

  143. 143

    Li, J., Qin, Z. & Liang, Z. The prosurvival role of autophagy in Resveratrol-induced cytotoxicity in human U251 glioma cells. BMC Cancer 9, 215 (2009).

    PubMed  PubMed Central  Google Scholar 

  144. 144

    Stein, M. et al. Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate 70, 1388–1394 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Poole, B. & Ohkuma, S. Effect of weak bases on the intralysosomal pH in mouse peritoneal macrophages. J. Cell Biol. 90, 665–669 (1981).

    CAS  PubMed  Google Scholar 

  146. 146

    Glaumann, H. & Ahlberg, J. Comparison of different autophagic vacuoles with regard to ultrastructure, enzymatic composition, and degradation capacity—formation of crinosomes. Exp. Mol. Pathol. 47, 346–362 (1987).

    CAS  PubMed  Google Scholar 

  147. 147

    Amaravadi, R. K. et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 117, 326–336 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Carew, J. S. et al. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood 110, 313–322 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Sotelo, J., Briceno, E. & Lopez-Gonzalez, M. A. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 144, 337–343 (2006).

    CAS  PubMed  Google Scholar 

  150. 150

    Lu, Z. et al. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J. Clin. Invest. 118, 3917–3929 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Amaravadi, R. K. & Thompson, C. B. The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin. Cancer Res. 13, 7271–7279 (2007).

    CAS  PubMed  Google Scholar 

  152. 152

    Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Mizushima, N., Yoshimori, T. & Levine, B. Methods in mammalian autophagy research. Cell 140, 313–326 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4, 151–175 (2008).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Joann Aaron (The University of Texas MD Anderson Cancer Center, USA) for scientific review and editing of this article.

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All authors were equally involved in the research of data and writing of the article, provided substantial contributions to the discussion of content, and reviewed and/or edited the manuscript before submission and in response to editorial queries.

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Correspondence to Filip Janku.

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Supplementary Box 1

Mechanistic details of the autophagy machinery (DOC 47 kb)

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Janku, F., McConkey, D., Hong, D. et al. Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol 8, 528–539 (2011). https://doi.org/10.1038/nrclinonc.2011.71

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