TRAIL and apoptosis induction by TNF-family death receptors

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand or Apo 2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family of ligands capable of initiating apoptosis through engagement of its death receptors. TRAIL selectively induces apoptosis of a variety of tumor cells and transformed cells, but not most normal cells, and therefore has garnered intense interest as a promising agent for cancer therapy. TRAIL is expressed on different cells of the immune system and plays a role in both T-cell- and natural killer cell-mediated tumor surveillance and suppression of suppressing tumor metastasis. Some mismatch-repair-deficient tumors evade TRAIL-induced apoptosis and acquire TRAIL resistance through different mechanisms. Death receptors, members of the TNF receptor family, signal apoptosis independently of the p53 tumor-suppressor gene. TRAIL treatment in combination with chemo- or radiotherapy enhances TRAIL sensitivity or reverses TRAIL resistance by regulating the downstream effectors. Efforts to identify agents that activate death receptors or block specific effectors may improve therapeutic design. In this review, we summarize recent insights into the apoptosis-signaling pathways stimulated by TRAIL, present our current understanding of the physiological role of this ligand and the potential of its application for cancer therapy and prevention.

TRAIL and its receptors

TRAIL is a type II transmembrane protein that was initially identified and cloned based on the sequence homology of its extracellular domain with CD95L (28% identical) and TNF (23% identical) (Wiley et al., 1995); however, its extracellular carboxy-terminal portion can be proteolytically cleaved from the cell surface in a vesicle-associated or in a soluble form (Mariani and Krammer, 1998; Monleon et al., 2001). Like most other TNF family members, TRAIL forms homotrimers that bind three receptor molecules, each at the interface between two of its subunits (Hymowitz et al., 1999; Mongkolsapaya et al., 1999). A Zn atom bound by cysteines in the trimeric ligand is essential for trimer stability and optimal biological activity (Bodmer et al., 2000). Functional studies showed that this ligand has a potent ability to trigger apoptosis in a variety of tumor cell lines, but not most normal cells, highlighting its potential therapeutic application in cancer treatment (Ashkenazi et al., 1999; Walczak et al., 1999; Jo et al., 2000; El-Deiry, 2001; Schmaltz et al., 2002; Seki et al., 2003). In contrast to other TNF family members, whose expressions are tightly regulated and are often only transiently expressed on activated cells, TRAIL mRNA is constitutively expressed in a wild range of tissues (Wiley et al., 1995). Although the main biological function of TRAIL seems to be the induction of apoptosis, the complete physiological role of this ligand is not yet fully understood. It appears likely that TRAIL expression on liver NK cells is regulated by IFN-γ secreted from NK cells in an autocrine manner, since a large portion of NK cells constitutively produce both TRAIL and IFN-γ in wild-type and T-cell-deficient mice (Takeda et al., 2001). Mouse gene knockout studies indicate that TRAIL has an important role in antitumor surveillance by immune cells (Cretney et al., 2002; Smyth et al., 2003), and mediates thymocyte apoptosis and is important in the induction of autoimmune diseases (Lamhamedi-Cherradi et al., 2003).

TRAIL induces apoptosis through interacting with its receptors (Ivanov et al., 2003; LeBlanc and Ashkenazi, 2003; Ozoren and El-Deiry, 2003). So far, four homologous human receptors for TRAIL have been identified (Figure 1), including DR4 (Pan et al., 1997a), KILLER/DR5 (Pan et al., 1997b; Sheridan et al., 1997; Walczak et al., 1997; Wu et al., 1997), TRID/DcR1/TRAIL-R3 (Degli-Esposti et al., 1997; Pan et al., 1997b; Sheridan et al., 1997), and TRAIL-R4/DcR2 (Degli-Esposti et al., 1997; Marsters et al., 1997), as well as a fifth soluble receptor called osteoprotegerin (OPG), which was identified initially as a receptor for RANKL/OPGL and was shown later to bind TRAIL (Emery et al., 1998). Both the death receptors DR4 and DR5 contain a conserved death domain (DD) motif and signal apoptosis. The other three receptors appear to act as ‘decoys’ for their ability to inhibit TRAIL-induced apoptosis when overexpressed. Decoy receptor 1 (DcR1) and DcR2 have close homology to the extracellular domains of DR4 and DR5. DcR2 has a truncated, nonfunctional cytoplasmic DD, while DcR1 lacks a cytosolic region and is anchored to the plasma membrane through a glycophospholipid moiety. The physiological relevance of OPG as a receptor for TRAIL is unclear, however, because the affinity for this ligand at physiological temperatures is very low (Truneh et al., 2000). A recent study suggests that cancer-derived OPG may be an important survival factor in hormone-resistant prostate cancer cells and there is a negative correlation between the levels of OPG and the capacity of TRAIL to induce apoptosis in prostate cancer cells that endogenously produced a high level of OPG (Holen et al., 2002).

Figure 1
figure1

TRAIL and its receptors. TRAIL is a homotrimeric ligand capable of interacting with the members of the TNF receptor family. The extracellular ligand binding of the receptors is characterized by various numbers of the cysteine-rich domain (CRD). Death receptors, DR5 and DR4, contain a DD in their intracellular region, which is essential for apoptosis signaling. Decoy receptors DcR1 and DcR2 compete with DR4 and DR5 for binding to TRAIL. OPG, a soluble receptor, is capable of binding to TRAIL with low affinity

Trail-induced apoptosis signaling

Two main signaling pathways have been delineated to initiate the apoptotic suicide program in mammalian cells, the intrinsic and extrinsic pathways (Ashkenazi A, 2002). The cell extrinsic pathway is initiated by members of the TNF superfamily. TRAIL has been shown to induce apoptosis through binding its respective receptors, DR4 and DR5. Ligation of TRAIL to its receptor results in trimerization of the receptor and clustering of the receptor's intracellular DD, leading to the formation of the death-inducing signaling complex (DISC). Trimerization of the DDs leads to the recruitment of an adaptor molecule, FADD, and subsequent binding and activation of caspase-8 and -10. Activated caspase-8 and -10 then cleave caspase-3, which in turn leads to cleavage of the death substrates (Figure 2). The cell intrinsic pathway triggers apoptosis in response to DNA damage, cell cycle checkpoint defects, mitotic catastroph hypoxia, loss of survival factors or other types of severe cell stresses. The pathway involves the activation of the proapoptotic arm of the Bcl-2 gene superfamily, which in turn engages the mitochondria to cause the release of apoptogenic factors such as cytochrome c and SMAC/DIABLO into the cytosol (Adams and Cory, 1998; Green, 2000; Hunt and Evan, 2001). In the cytosol, cytochrome c binds the adaptor APAF-1, forming an ‘apoptosome’ that activates the apoptosis-initiating protease caspase-9. In turn, caspase-9 activates ‘executioner’ protease caspase-3, -6, and -7. SMAC/DIABLO promotes apoptosis by binding to inhibitor of apoptosis (IAP) proteins and preventing these factors from attenuating caspase activation (Du et al., 2000; Verhagen et al., 2000) (Figure 2). The intrinsic and extrinsic apoptosis signaling pathways communicate with each other. Caspase-8 has been shown to cleave the proapoptotic Bcl-2 family member Bid. The cleavage of Bid by caspase-8 and the translocation of truncated Bid to the mitochondria to promote cytochrome c release through interaction with Bax and Bak provide a plausible mechanistic link between the extrinsic and intrinsic pathways (Green, 2000). This apparently amplifies the apoptotic signal following death receptor activation, and different cell types may be more reliant on this amplification pathway than others (Fulda et al., 2001). Conversely, activators of the intrinsic pathway can sensitize cells to extrinsic death ligands.

Figure 2
figure2

TRAIL-induced apoptosis signaling pathways. Binding of TRAIL and trimerization of TRAIL death receptors leads to recruitment of Fas-associated death receptor (FADD), an adaptor molecule that recruits and activates caspase-8. FLIP interferes with the generation of active caspase-8. In some cell types (type I), activation of caspase-8 is sufficient to trigger apoptosis, whereas, in other cell types (type II), amplification of the extrinsic pathway through the mitochondrial pathway is needed to commit the cells to apoptosis. The cleavage of Bid by caspase-8 and the translocation of the truncated bid to mitochondria provide a mechanistic link between the extrinsic and intrinsic pathways

The relative contribution of death receptor versus mitochondrial pathways in apoptosis may vary but may also reflect the existence of two different cell types with respect to CD95 signaling. In type I cells, caspase-8 activation sufficient to kill cells occurs as a direct consequence of death receptor ligation, with activating downstream (effector) procaspases such as caspase-3. This step is independent of the mitochondria and is not blocked by overexpression of Bcl-2. In contrast, type II (intrinsic) cell death is dependent on the amplification of death receptor signals via the mitochondrial pathway controlled by Bcl-2. At the molecular level, these two cell types differ principally in the amount of caspase-8 recruited to CD95 via FADD to form the DISC. Whereas type I cells effectively activate caspase 8 recruited to the DISC in response to CD95 antibodies, type II cells do not, and are thus dependent on stimulation of the intrinsic apoptotic pathway to undergo cell death. Mitochondrial release of Cytochrome c occurs in both type I and type II cells, but are dispensable for the death of type I cells (Figure 2). Previous studies in cell lines and in vivo have demonstrated the existence of type I and type II cell lines in response to FasL (Scaffidi et al., 1998) or TRAIL (Ozoren et al., 2000; Burns and El-Deiry, 2001; Ozoren and El-Deiry, 2002).

TRAIL sensitivity and resistance

When compared with nontransformed cells, cancer cells are more sensitive to TRAIL-induced apoptosis following exposure to TRAIL treatment. Selective sensitization of tumor cells to TRAIL-induced apoptosis can often be attributed to greater expression of the TRAIL receptor (Zhang et al., 1999). However, when death receptors for TRAIL were identified, it was found that the mRNA expression of the receptors was also widely distributed in both normal and malignant tissues (Chaudhary et al., 1997). The discovery of two decoy receptors that could bind TRAIL, but that were unable to induce apoptosis, seemed to explain the paradox. Again, it was assumed that normal cells would express decoy receptors, but cancer cells would not (Gura, 1997). It is not fully clear how widespread is the decoy receptor surface expression in cancer or normal cells, or how these receptors modulate TRAIL sensitivity (Hersey and Zhang, 2001; Kim et al., 2000).

The lack of caspase-8 and -10 expression in a large subset of neuroblastoma (NB) cell lines provides an explanation for the findings that these cell lines are resistant to TRAIL-mediated apoptosis (Eggert et al., 2001) (Figure 3). However, loss of caspase-8 and/or -10 expression might not be the sole factor responsible for conferring resistance to TRAIL-induced apoptosis in NB cells. Regulation of the TRAIL system in NB is most likely also conferred by multiple agonistic and inhibitory receptors, a complex intracellular signaling mechanism involving a number of signaling adaptors and activation of inhibitory molecules (Eggert et al., 2001).

Figure 3
figure3

Sensitivity and resistance to TRAIL-mediated apoptosis. TRAIL kills cancer and transformed cells but not most normal cells. There are multiple mechanisms that have been described (see text). Cancer cells may develop resistance to TRAIL if they lose expression of death receptors, caspase-8/10, or overexpress either FLIP or Bcl2/Bcl-XL. Chemotherapy or radiation can combine with TRAIL to achieve synergistic killing or reverse TRAIL resistance through upregulation of p53 transcriptional target genes such as DR5

The cellular FLICE-inhibitory proteins (c-FLIPs) have sequence homology to caspase-8 and -10, but lack protease activity (Tschopp et al., 1998). Therefore, the recruitment of FLIP to the DISC in place of caspase-8 or -10 blocks their activation and consequently confers TRAIL resistance (Figure 3). The function of FLIP is, however, not entirely clear. Burns and El-Deiry (2001) found that only the short form of the c-FLIP could confer TRAIL resistance to a sensitive colon carcinoma cell line. It has been shown that degradation of FLIP apparently sensitizes tumor cells to TRAIL-induced apoptosis (Kim et al., 2002), and others have found a correlation between FLIP levels and TRAIL resistance (Griffith et al., 1998; Kim et al., 2000). However, recent experiments suggest that FLIP can actually promote caspase-8 activation in response to Fas engagement (Chang et al., 2002). Therefore, it is still ambiguous whether FLIP is closely related to the level of apoptosis that is induced by TRAIL.

The proapoptotic Bcl-2 family member Bax is a frequent target for mutation in a subset of mismatch-repair (MMR)-deficient human tumors. It has been found that Bax is required for TRAIL-induced apoptosis of certain cancer cell lines, possibly by allowing the release of second mitochondria-derived activator of caspases (Smac)/direct IAP-binding family protein with low pH (DIABLO) and antagonizing the IAP protein family (Deng et al., 2002) (Figures 2, 3). Bax inactivation in MMR-deficient tumors can cause resistance to TRAIL (Burns and El-Deiry, 2001; LeBlanc et al., 2002), and reintroduction of Bax into Bax-deficient cells restored TRAIL sensitivity (Deng et al., 2002). Recent studies have indicated that sequential combination of TRAIL with chemotherapy could overcome the TRAIL resistance (LeBlanc et al., 2002). However, the mechanisms of reversal TRAIL resistance remain unclear. Wang and El-Deiry found that the tumor suppressor p53 was required for sensitizing the Bax-deficient tumors to TRAIL by chemotherapy, and the p53 downstream transcriptional target gene DR5 contributes significantly to TRAIL sensitization, whereas Bak plays a minor role. These studies elucidate a mechanism for restoration of TRAIL sensitivity in MMR-deficient Bax−/− human cancers through p53-dependent activation of DR5 and reconstitution of a type I death pathway (Wang and El-Deiry, in press).

There are several other factors that might modulate the sensitivity of the cells to TRAIL. More recent works have identified interleukine 8 as an inhibitor for TRAIL-induced apoptosis in the ovarian carcinoma cell line OVCAR3 (Abdollahi et al., 2003). NF-κB induces upregulation of FLIP, Bcl-XL, and XIAP, and may exert protection against cell death through these molecules. In contrast, specific downregulation of NFκB by inactivation of I-κB kinase significantly sensitizes the cells to TRAIL (Ravi and Bedi, 2002). It has been reported that protein kinase C (PKC) activation specifically inhibits the recruitment of key obligatory DD-containing adaptor proteins to their respective membrane-associated signaling complexes, thereby modulating TRAIL-induced apoptosis (Harper et al., 2003) and mitogen-activated protein kinase (MAPK) (Frese et al., 2003), and Akt (Thakkar et al., 2001) have also been found to affect the TRAIL sensitivity.

TRAIL and its potential for cancer therapy

The soluble recombinant TRAIL is of interest for cancer therapy for a number of reasons. There are few agents that are truly cancer cell-specific in terms of efficacy or cell death induction. TRAIL is a rare example of such molecules that kill many transformed cells but not most normal cells (Ashkenazi and Dixit, 1998). Importantly, administration of soluble recombinant TRAIL in experimental animals, including mice and primates, induces significant tumor regression without systemic toxicity (Ashkenazi et al., 1999; Walczak et al., 1999). Apoptosis induction in response to most DNA-damaging drugs usually requires the function of the tumor suppressor p53, which engages primarily the intrinsic apoptotic-signaling pathway (Figure 3). However, in most human cancers, tumor progression as well as conventional treatments eventually select for tumor cells in which p53 is inactivated, resulting in resistance to therapy. TRAIL induces apoptosis in a variety of cancer cell lines regardless of p53 status, and therefore it might be a useful therapeutic strategy, particularly in cells in which the p53-response pathway has been inactivated, thus helping to circumvent resistance to chemo- and radiotherapy. Although one of the attractive features of TRAIL is its ability to kill cancers with mutations in the p53 gene, the combination of TRAIL with chemotherapeutic agents has been found to be particularly effective in killing cancers with wild-type p53, presumably through induction of DR5 expression (Nagane et al., 2001; Wang and El-Deiry, in press) (Figure 3). In addition, Bax mutation in MMR-deficient tumors can cause resistance to TRAIL therapy, but pre-exposure to chemotherapy rescues the tumor sensitivity (LeBlanc et al., 2002; Wang and El-Deiry, in press). In vitro, prior exposure of Bax-deficient cells to topoisomerase inhibitors including CPT-11 and etoposide restores TRAIL sensitivity, mainly by upregulating DR5 (Wang and El-Deiry, in press). Thus, targeting of DR5 in cancer cells might be a useful therapeutic strategy. In tumors that retain some responsiveness to conventional therapy or radiation, upregulation of DR5 might lead to synergistic apoptosis activation as well as reduce the probability that tumor cells will become resistant to treatment. In tumors that have lost p53 function, DR5 targeting might therefore help circumvent resistance to chemotherapy and radiotherapy. Agents so far available to upregulate DR5 expression are largely those that activate p53. Efforts to identify agents that upregulate DR5 independently of p53 may be useful in TRAIL-based cancer therapies, especially for killing the tumor cells that are resistant to conventional therapies. Recent progress in molecular imaging such as bioluminescence imaging is beginning to accelerate the pace of drug development. The identification of small molecules that are involved in the regulation of DR5 by large-scale screening of chemical libraries using bioluminescence imaging might be a useful strategy to discover and test agents that could lead to synergistic apoptosis activation.

Enhancement of the mitochondrial pathways to apoptosis offers more immediate ways of increasing sensitivity to TRAIL. Antisense molecules to Bcl2 are now in phase III clinical trials. Preclinical studies demonstrated that the antisense Bcl2 oligonucleotide alone was superior to standard chemotherapy for Merkel cell carcinoma and enhanced apoptosis in other tumor models when used in combination with chemotherapy (Jansen et al., 1998; Banerjee, 2001). Another approach to enhance the mitochondrial death pathway is to increase the expression of APAF-1, which can be achieved by the demethylating agent 5-aza-2-deoxycytidine (Soengas et al., 2001). Since XIAP blocks apoptosis at the effector phase, a point where multiple signaling pathways converge, strategies targeting XIAP may prove effective to overcome resistance. Actinomycin D has been shown to downregulate a number of proteins that are known to inhibit apoptosis. XIAP seems to be particularly sensitive to pretreatment with actinomycin D (Zhang et al., 2001), and might provide one explanation for its ability to sensitize melanoma cells to TRAIL-induced apoptosis (Zhang et al., 2001). Smac was identified as a protein that is released from mitochondria in response to apoptotic stimuli, and it has been reported that Smac agonists sensitize TRAIL-induced apoptosis and induce the regression of malignant glioma in vivo (Fulda et al., 2002).

Agents that inhibit the activation of NFκB have been the focus of much attention as anticancer agents. Proteasome inhibitors such as PS341, which prevent degradation of IκBα and other proteins such as p53, are in clinical trials (Teicher et al., 1999). More recently, the proteasome inhibitor PS-341 has been found to overcome TRAIL resistance in Bax and caspase-9-negative or Bcl-XL-overexpressing cells. PS-341 treatment elevates the levels of TRAIL receptors DR4 and DR5, and this increase in receptor protein levels is associated with the ubiquitination of the DR5 protein, therefore sensitizing resistant prostate, colon, and bladder cancer cells to TRAIL-induced apoptosis (Johnson et al., 2003). Some compounds such as CP31398 (Foster et al., 1999; Takimoto et al., 2002; Wang et al., 2003) and Prima1 (Bykov et al., 2002) have been reported to cause cell death of tumors that carry mutated p53 and are able to restore a wild-type epitope in mutated p53. CP31398 appears to alter p53 selectivity towards death receptor induction, and this may be of interest for strategies combining this agent with death ligands such as TRAIL (Takimoto et al., 2002; Wang et al., 2003).

Besides using the recombinant ligand, several gene therapy approaches are currently being developed to target tumor cells specifically. A TRAIL-expressing adenoviral vector has been recently shown to cause direct tumor cell killing, as well as a potent bystander effect through presentation of TRAIL by transduced normal cells (Lee et al., 2002). An adenoviral vector expressing the GFP/TRAIL fusion gene from the hTERT promoter elicited high levels of transgene expression and apoptosis in a variety of breast cancer cell lines. Furthermore, treatment with Ad/gTRAIL effectively induced apoptosis in malignant cells but not in normal human primary hepatocytes in vitro, suppressed tumor growth and prolonged duration of survival in vivo (Lin et al., 2002). Although these are promising therapies, they largely depend on the efficient infection of the tumor and avoidance of immune clearance to be effective. Therefore, the current generation of adenoviral vectors appears to be limited to local therapy (McCormick, 2001; Armeanu et al., 2003).

Conclusions and perspective

TRAIL is a potent inducer of apoptosis that acts through a complicated receptor system. Much has been learned about the endogenous biochemical pathways leading to TRAIL-induced apoptosis in cancer cells. This ligand appears to play an important role in immune surveillance by cells of the innate immune system against viral infection and malignant transformation. Owing to the selectivity of the soluble recombinant TRAIL towards transformed cells but not most normal cells, this ligand remains promising as a potential cancer therapeutic agent. Defining the context in which TRAIL may eliminate or spare normal tissues and why normal cells are generally resistant to TRAIL is also of great importance when considering manipulating the TRAIL pathway in novel cancer therapy. Efforts to identify agents that target death receptors directly or which confer synergy with TRAIL may be useful for cancer therapy.

References

  1. Abdollahi T, Robertson NM, Abdollahi A and Litwack G . (2003). Cancer Res., 63, 4521–4526.

  2. Adams JM and Cory S . (1998). Science, 281, 1322–1326.

  3. Armeanu S, Lauer UM, Smirnow I, Schenk M, Weiss TS, Gregor M and Bitzer M . (2003). Cancer Res., 63, 2369–2372.

  4. Ashkenazi A . (2002). Nat. Rev. Cancer, 2, 420–430.

  5. Ashkenazi A and Dixit VM . (1998). Science, 281, 1305–1308.

  6. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z and Schwall RH . (1999). J. Clin. Invest., 104, 155–162.

  7. Banerjee D . (2001). Curr. Opin. Investig. Drugs, 2, 574–580.

  8. Bodmer JL, Meier P, Tschopp J and Schneider P . (2000). J. Biol. Chem., 275, 20632–20637.

  9. Burns TF and El-Deiry WS . (2001). J. Biol. Chem., 276, 37879–37886.

  10. Bykov VJ, Issaeva N, Selivanova G and Wiman KG . (2002). Carcinogenesis, 23, 2011–2018.

  11. Chang DW, Xing Z, Pan Y, Algeciras-Schimnich A, Barnhart BC, Yaish-Ohad S, Peter ME and Yang X . (2002). EMBO J., 21, 3704–3714.

  12. Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J and Hood L . (1997). Immunity, 7, 821–830.

  13. Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ and Smyth MJ . (2002). J. Immunol., 168, 1356–1361.

  14. Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA and Goodwin RG . (1997). Immunity, 7, 813–820.

  15. Deng Y, Lin Y and Wu X . (2002). Genes Dev., 16, 33–45.

  16. Du C, Fang M, Li Y, Li L and Wang X . (2000). Cell, 102, 33–42.

  17. Eggert A, Grotzer MA, Zuzak TJ, Wiewrodt BR, Ho R, Ikegaki N and Brodeur GM . (2001). Cancer Res., 61, 1314–1319.

  18. El-Deiry WS . (2001). Cell Death Differ., 8, 1066–1075.

  19. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC and Young PR . (1998). J. Biol. Chem., 273, 14363–14367.

  20. Foster BA, Coffey HA, Morin MJ and Rastinejad F . (1999). Science, 286, 2507–2510.

  21. Frese S, Pirnia F, Miescher D, Krajewski S, Borner MM, Reed JC and Schmid RA . (2003). Oncogene, 22, 5427–5435.

  22. Fulda S, Meyer E, Friesen C, Susin SA, Kroemer G and Debatin KM . (2001). Oncogene, 20, 1063–1075.

  23. Fulda S, Wick W, Weller M and Debatin KM . (2002). Nat. Med., 8, 808–815.

  24. Green DR . (2000). Cell, 102, 1–4.

  25. Griffith TS, Chin WA, Jackson GC, Lynch DH and Kubin ME. (1998). J. Immunol., 161, 2833–2840.

  26. Gura T . (1997). Science, 277, 768.

  27. Harper N, Hughes MA, Farrow SN, Cohen GM and MacFarlane M . (2003). J. Biol. Chem., (in press).

  28. Hersey P and Zhang XD . (2001). Nat. Rev. Cancer, 1, 142–150.

  29. Holen I, Croucher PI, Hamdy FC and Eaton CL . (2002). Cancer Res., 62, 1619–1623.

  30. Hunt A and Evan G . (2001). Science, 293, 1784–1785.

  31. Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O'Connell M, Kelley RF, Ashkenazi A and de Vos AM . (1999). Mol. Cell, 4, 563–571.

  32. Ivanov VN, Bhoumik A and Ronai Z . (2003). Oncogene, 22, 3152–3161.

  33. Jansen B, Schlagbauer-Wadl H, Brown BD, Bryan RN, van Elsas A, Muller M, Wolff K, Eichler HG and Pehamberger H . (1998). Nat. Med., 4, 232–234.

  34. Jo M, Kim TH, Seol DW, Esplen JE, Dorko K, Billiar TR and Strom SC . (2000). Nat. Med., 6, 564–567.

  35. Johnson TR, Stone K, Nikrad M, Yeh T, Zong WX, Thompson CB, Nesterov A and Kraft AS . (2003). Oncogene, 22, 4953–4963.

  36. Kim K, Fisher MJ, Xu SQ and El-Deiry WS . (2000). Clin. Cancer Res., 6, 335–346.

  37. Kim Y, Suh N, Sporn M and Reed JC . (2002). J. Biol. Chem., 277, 22320–22329.

  38. Lamhamedi-Cherradi SE, Zheng SJ, Maguschak KA, Peschon J and Chen YH . (2003). Nat. Immunol., 4, 255–260.

  39. LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, Schow P, Fong S, Schwall R, Sinicropi D and Ashkenazi A . (2002). Nat. Med., 8, 274–281.

  40. LeBlanc HN and Ashkenazi A . (2003). Cell Death Differ., 10, 66–75.

  41. Lee J, Hampl M, Albert P and Fine HA . (2002). Neoplasia, 4, 312–323.

  42. Lin T, Huang X, Gu J, Zhang L, Roth JA, Xiong M, Curley SA, Yu Y, Hunt KK and Fang B . (2002). Oncogene, 21, 8020–8028.

  43. Mariani SM and Krammer PH . (1998). Eur. J. Immunol., 28, 1492–1498.

  44. Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, Yuan J, Gurney A, Goddard AD, Godowski P and Ashkenazi A . (1997). Curr. Biol., 7, 1003–1006.

  45. McCormick F . (2001). Nat. Rev. Cancer., 1, 130–141.

  46. Mongkolsapaya J, Grimes JM, Chen N, Xu XN, Stuart DI, Jones EY and Screaton GR . (1999). Nat. Struct. Biol., 6, 1048–1053.

  47. Monleon I, Martinez-Lorenzo MJ, Monteagudo L, Lasierra P, Taules M, Iturralde M, Pineiro A, Larrad L, Alava MA, Nava J and Anel A . (2001). J. Immunol., 167, 6736–6744.

  48. Nagane M, Huang HJ and Cavenee WK . (2001). Apoptosis, 6, 191–197.

  49. Ozoren N and El-Deiry W . (2003). Semin. Cancer Biol., 13, 135–147.

  50. Ozoren N and El-Deiry WS . (2002). Neoplasia, 4, 551–557.

  51. Ozoren N, Kim K, Burns TF, Dicker DT, Moscioni AD and El-Deiry WS . (2000). Cancer Res., 60, 6259–6265.

  52. Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J and Dixit VM . (1997a). Science, 276, 111–113.

  53. Pan G, Ni J, Wei YF, Yu G, Gentz R and Dixit VM . (1997b). Science, 277, 815–818.

  54. Ravi R and Bedi A . (2002). Cancer Res., 62, 1583–1587.

  55. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH and Peter ME . (1998). EMBO J., 17, 1675–1687.

  56. Schmaltz C, Alpdogan O, Kappel BJ, Muriglan SJ, Rotolo JA, Ongchin J, Willis LM, Greenberg AS, Eng JM, Crawford JM, Murphy GF, Yagita H, Walczak H, Peschon JJ and van den Brink MR . (2002). Nat. Med., 8, 1433–1437.

  57. Seki N, Hayakawa Y, Brooks AD, Wine J, Wiltrout RH, Yagita H, Tanner JE, Smyth MJ and Sayers TJ . (2003). Cancer Res., 63, 207–213.

  58. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P and Ashkenazi A . (1997). Science, 277, 818–821.

  59. Smyth MJ, Takeda K, Hayakawa Y, Peschon JJ, van den Brink MR and Yagita H . (2003). Immunity, 18, 1–6.

  60. Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C and Lowe SW . (2001). Nature, 409, 207–211.

  61. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, Iwakura Y, Yagita H and Okumura K . (2001). Nat. Med., 7, 94–100.

  62. Takimoto R, Wang W, Dicker DT, Rastinejad F, Lyssikatos J and El-Deiry WS . (2002). Cancer Biol. Ther., 1, 47–55.

  63. Teicher BA, Ara G, Herbst R, Palombella VJ and Adams J . (1999). Clin. Cancer Res., 5, 2638–2645.

  64. Thakkar H, Chen X, Tyan F, Gim S, Robinson H, Lee C, Pandey SK, Nwokorie C, Onwudiwe N and Srivastava RK . (2001). J. Biol. Chem., 276, 38361–38369.

  65. Truneh A, Sharma S, Silverman C, Khandekar S, Reddy MP, Deen KC, McLaughlin MM, Srinivasula SM, Livi GP, Marshall LA, Alnemri ES, Williams WV and Doyle ML . (2000). J. Biol. Chem., 275, 23319–23325.

  66. Tschopp J, Irmler M and Thome M . (1998). Curr. Opin. Immunol., 10, 552–558.

  67. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ and Vaux DL . (2000). Cell, 102, 43–53.

  68. Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG and Rauch CT . (1997). EMBO J., 16, 5386–5397.

  69. Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith CA, Smolak P, Goodwin RG, Rauch CT, Schuh JC and Lynch DH . (1999). Nat. Med., 5, 157–163.

  70. Wang S and El-Deiry . (2003). Proc. Natl. Acad. Sci. USA., (in press).

  71. Wang W, Takimoto R, Rastinejad F and El-Deiry WS . (2003). Mol. Cell. Biol., 23, 2171–2181.

  72. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA and Goodwin RG . (1995). Immunity, 3, 673–682.

  73. Wu GS, Burns TF, McDonald III ER, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G and El-Deiry WS . (1997). Nat. Genet., 17, 141–143.

  74. Zhang XD, Franco A, Myers K, Gray C, Nguyen T and Hersey P . (1999). Cancer Res., 59, 2747–2753.

  75. Zhang XD, Zhang XY, Gray CP, Nguyen T and Hersey P . (2001). Cancer Res., 61, 7339–7348.

Download references

Acknowledgements

WS El-Deiry is an Assistant Investigator of the Howard Hughes Medical Institute.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Wafik S El-Deiry.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, S., El-Deiry, W. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22, 8628–8633 (2003). https://doi.org/10.1038/sj.onc.1207232

Download citation

Keywords

  • tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)
  • tumor necrosis factor receptor family
  • p53
  • apoptosis
  • cancer therapy

Further reading

Search

Quick links