Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Mechanisms of resistance to TRAIL-induced apoptosis in cancer

Cancer Gene Therapy volume 12, pages 228–237 (2005)Cite this article

Abstract

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anticancer agent. However, considerable numbers of cancer cells, especially some highly malignant tumors, are resistant to apoptosis induction by TRAIL, and some cancer cells that were originally sensitive to TRAIL-induced apoptosis can become resistant after repeated exposure (acquired resistance). Understanding the mechanisms underlying such resistance and developing strategies to overcome it are important for the successful use of TRAIL for cancer therapy. Resistance to TRAIL can occur at different points in the signaling pathways of TRAIL-induced apoptosis. Dysfunctions of the death receptors DR4 and DR5 due to mutations can lead to resistance. The adaptor protein Fas-associated death domain (FADD) and caspase-8 are essential for assembly of the death-inducing signaling complex, and defects in either of these molecules can lead to TRAIL resistance. Overexpression of cellular FADD-like interleukin-1β-converting enzyme-inhibitory protein (cFLIP) correlates with TRAIL resistance in several types of cancer. Overexpression of Bcl-2 or Bcl-XL, loss of Bax or Bak function, high expression of inhibitor of apoptosis proteins, and reduced release of second mitochondria-derived activator of caspases (Smac/Diablo) from the mitochondria to the cytosol have all been reported to result in TRAIL resistance in mitochondria-dependent type II cancer cells. Finally, activation of different subunits of mitogen-activated protein kinases or nuclear factor-kappa B can lead to development of either TRAIL resistance or apoptosis in certain types of cancer cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Pitti RM, Marsters SA, Ruppert S, et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996;271:12687–12690.

    Article  CAS  PubMed  Google Scholar 

  2. Lin T, Gu J, Zhang L, et al. Targeted expression of green fluorescent protein/tumor necrosis factor-related apoptosis-inducing ligand fusion protein from human telomerase reverse transcriptase promoter elicits antitumor activity without toxic effects on primary human hepatocytes. Cancer Res. 2002;62:3620–3625.

    CAS  PubMed  Google Scholar 

  3. Armeanu S, Lauer UM, Smirnow I, et al. Adenoviral gene transfer of tumor necrosis factor-related apoptosis-inducing ligand overcomes an impaired response of hepatoma cells but causes severe apoptosis in primary human hepatocytes. Cancer Res. 2003;63:2369–2372.

    CAS  PubMed  Google Scholar 

  4. Gu J, Zhang L, Huang X, et al. A novel single tetracycline-regulative adenoviral vector for tumor-specific Bax gene expression and cell killing in vitro and in vivo. Oncogene. 2002;21:4757–4764.

    CAS  PubMed  Google Scholar 

  5. Hinz S, Trauzold A, Boenicke L, et al. Bcl-XL protects pancreatic adenocarcinoma cells against CD95- and TRAIL-receptor-mediated apoptosis. Oncogene. 2000;19:5477–5486.

    CAS  PubMed  Google Scholar 

  6. Fulda S, Kufer MU, Meyer E, et al. Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene. 2001;20:5865–5877.

    CAS  PubMed  Google Scholar 

  7. Eggert A, Grotzer MA, Zuzak TJ, et al. Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Cancer Res. 2001;61:1314–1319.

    CAS  PubMed  Google Scholar 

  8. Zhang L, Gu J, Lin T, et al. Mechanisms involved in development of resistance to adenovirus-mediated proapoptotic gene therapy in DLD1 human colon cancer cell line. Gene Therapy. 2002;9:1262–1270.

    CAS  PubMed  Google Scholar 

  9. Pan G, O’Rourke K, Chinnaiyan AM, et al. The receptor for the cytotoxic ligand TRAIL. Science. 1997;276:111–113.

    Article  CAS  PubMed  Google Scholar 

  10. Walczak H, Degli-Esposti MA, Johnson RS, et al. TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J. 1997;16:5386–5397.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Daniel PT, Wieder T, Sturm I, et al. The kiss of death: promises and failures of death receptors and ligands in cancer therapy. Leukemia. 2001;15:1022–1032.

    CAS  PubMed  Google Scholar 

  12. Liu X, Kim CN, Yang J, et al. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86:147–157.

    Article  CAS  PubMed  Google Scholar 

  13. Kluck RM, Bossy-Wetzel E, Green DR, et al. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science. 1997;275:1132–1136.

    Article  CAS  PubMed  Google Scholar 

  14. Micheau O, Tschopp J . Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181–190.

    CAS  PubMed  Google Scholar 

  15. Chaudhary PM, Eby M, Jasmin A, et al. Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Immunity. 1997;7:821–830.

    CAS  PubMed  Google Scholar 

  16. Schneider P, Thome M, Burns K, et al. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity. 1997;7:831–836.

    CAS  PubMed  Google Scholar 

  17. Degli-Esposti MA, Smolak PJ, Walczak H, et al. Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J Exp Med. 1997;186:1165–1170.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Degli-Esposti MA, Dougall WC, Smolak PJ, et al. The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity. 1997;7:813–820.

    Article  CAS  PubMed  Google Scholar 

  19. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998;273:14363–14367.

    Article  CAS  PubMed  Google Scholar 

  20. Pan G, Ni J, Wei YF, et al. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science. 1997;277:815–818.

    CAS  PubMed  Google Scholar 

  21. Sheridan JP, Marsters SA, Pitti RM, et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science. 1997;277:818–821.

    CAS  PubMed  Google Scholar 

  22. Griffith TS, Chin WA, Jackson GC, et al. Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol. 1998;161:2833–2840.

    CAS  PubMed  Google Scholar 

  23. Fisher MJ, Virmani AK, Wu L, et al. Nucleotide substitution in the ectodomain of trail receptor DR4 is associated with lung cancer and head and neck cancer. Clin Cancer Res. 2001;7:1688–1697.

    CAS  PubMed  Google Scholar 

  24. Kim K, Fisher MJ, Xu SQ, et al. Molecular determinants of response to TRAIL in killing of normal and cancer cells. Clin Cancer Res. 2000;6:335–346.

    CAS  PubMed  Google Scholar 

  25. Ozoren N, Fisher MJ, Kim K, et al. Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance. Int J Oncol. 2000;16:917–925.

    CAS  PubMed  Google Scholar 

  26. Shin MS, Kim HS, Lee SH, et al. Mutations of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers. Cancer Res. 2001;61:4942–4946.

    CAS  PubMed  Google Scholar 

  27. Lee SH, Shin MS, Kim HS, et al. Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin's lymphoma. Oncogene. 2001;20:399–403.

    CAS  PubMed  Google Scholar 

  28. Pai SI, Wu GS, Ozoren N, et al. Rare loss-of-function mutation of a death receptor gene in head and neck cancer. Cancer Res. 1998;58:3513–3518.

    CAS  PubMed  Google Scholar 

  29. Lee SH, Shin MS, Kim HS, et al. Alterations of the DR5/TRAIL receptor 2 gene in non-small cell lung cancers. Cancer Res. 1999;59:5683–5686.

    CAS  PubMed  Google Scholar 

  30. Jeng YM, Hsu HC . Mutation of the DR5/TRAIL receptor 2 gene is infrequent in hepatocellular carcinoma. Cancer Lett. 2002;181:205–208.

    CAS  PubMed  Google Scholar 

  31. Kischkel FC, Hellbardt S, Behrmann I, et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995;14:5579–5588.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. MacFarlane M, Ahmad M, Srinivasula SM, et al. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. J Biol Chem. 1997;272:25417–25420.

    CAS  PubMed  Google Scholar 

  33. Petak I, Vernes R, Szucs KS, et al. A caspase-8-independent component in TRAIL/Apo-2L-induced cell death in human rhabdomyosarcoma cells. Cell Death Differ. 2003;10:729–739.

    CAS  PubMed  Google Scholar 

  34. Wajant H, Johannes FJ, Haas E, et al. Dominant-negative FADD inhibits TNFR60-, Fas/Apo1- and TRAIL-R/Apo2-mediated cell death but not gene induction. Curr Biol. 1998;8:113–116.

    CAS  PubMed  Google Scholar 

  35. Kuang AA, Diehl GE, Zhang J, et al. FADD is required for DR4- and DR5-mediated apoptosis: lack of trail-induced apoptosis in FADD-deficient mouse embryonic fibroblasts. J Biol Chem. 2000;275:25065–25068.

    CAS  PubMed  Google Scholar 

  36. Yeh WC, Pompa JL, McCurrach ME, et al. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science. 1998;279:1954–1958.

    CAS  PubMed  Google Scholar 

  37. Bodmer JL, Holler N, Reynard S, et al. TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol. 2000;2:241–243.

    CAS  PubMed  Google Scholar 

  38. Seol DW, Li J, Seol MH, et al. Signaling events triggered by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL): caspase-8 is required for TRAIL-induced apoptosis. Cancer Res. 2001;61:1138–1143.

    CAS  PubMed  Google Scholar 

  39. Sprick MR, Rieser E, Stahl H, et al. Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8. EMBO J. 2002;21:4520–4530.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Lacour S, Micheau O, Hammann A, et al. Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC assembly in HT29 human colon cancer cells. Oncogene. 2003;22:1807–1816.

    CAS  PubMed  Google Scholar 

  41. Secchiero P, Milani D, Gonelli A, et al. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF-alpha promote the NF-kappaB-dependent maturation of normal and leukemic myeloid cells. J Leukoc Biol. 2003;74:223–232.

    CAS  PubMed  Google Scholar 

  42. Chun HJ, Zheng L, Ahmad M, et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002;419:395–399.

    CAS  PubMed  Google Scholar 

  43. Wang J, Chun HJ, Wong W, et al. Caspase-10 is an initiator caspase in death receptor signaling. Proc Natl Acad Sci USA. 2001;98:13884–13888.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kischkel FC, Lawrence DA, Tinel A, et al. Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. J Biol Chem. 2001;276:46639–46646.

    CAS  PubMed  Google Scholar 

  45. Yang X, Merchant MS, Romero ME, et al. Induction of caspase 8 by interferon gamma renders some neuroblastoma (NB) cells sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in NB. Cancer Res. 2003;63:1122–1129.

    CAS  PubMed  Google Scholar 

  46. Teitz T, Wei T, Valentine MB, et al. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med. 2000;6:529–535.

    CAS  PubMed  Google Scholar 

  47. Hopkins-Donaldson S, Ziegler A, Kurtz S, et al. Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation. Cell Death Differ. 2003;10:356–364.

    CAS  PubMed  Google Scholar 

  48. Krueger A, Baumann S, Krammer PH, et al. FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol. 2001;21:8247–8254.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Goltsev YV, Kovalenko AV, Arnold E, et al. CASH, a novel caspase homologue with death effector domains. J Biol Chem. 1997;272:19641–19644.

    CAS  PubMed  Google Scholar 

  50. Han DK, Chaudhary PM, Wright ME, et al. MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death. Proc Natl Acad Sci USA. 1997;94:11333–11338.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Inohara N, Koseki T, Hu Y, et al. CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis. Proc Natl Acad Sci USA. 1997;94:10717–10722.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Shu HB, Halpin DR, Goeddel DV . Casper is a FADD- and caspase-related inducer of apoptosis. Immunity. 1997;6:751–763.

    CAS  PubMed  Google Scholar 

  53. Hu S, Vincenz C, Ni J, et al. I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD-95-induced apoptosis. J Biol Chem. 1997;272:17255–17257.

    CAS  PubMed  Google Scholar 

  54. Irmler M, Thome M, Hahne M, et al. Inhibition of death receptor signals by cellular FLIP. Nature. 1997;388:190–195.

    CAS  PubMed  Google Scholar 

  55. Rasper DM, Vaillancourt JP, Hadano S, et al. Cell death attenuation by ‘Usurpin’, a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. Cell Death Differ. 1998;5:271–288.

    CAS  PubMed  Google Scholar 

  56. Srinivasula SM, Ahmad M, Ottilie S, et al. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. J Biol Chem. 1997;272:18542–18545.

    CAS  PubMed  Google Scholar 

  57. Siegel RM, Martin DA, Zheng L, et al. Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis. J Cell Biol. 1998;141:1243–1253.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Kataoka T, Schroter M, Hahne M, et al. FLIP prevents apoptosis induced by death receptors but not by perforin/granzyme B, chemotherapeutic drugs, and gamma irradiation. J Immunol. 1998;161:3936–3942.

    CAS  PubMed  Google Scholar 

  59. Krueger A, Schmitz I, Baumann S, et al. Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J Biol Chem. 2001;276:20633–20640.

    CAS  PubMed  Google Scholar 

  60. Ryu BK, Lee MG, Chi SG, et al. Increased expression of cFLIP(L) in colonic adenocarcinoma. J Pathol. 2001;194:15–19.

    CAS  PubMed  Google Scholar 

  61. Bullani RR, Huard B, Viard-Leveugle I, et al. Selective expression of FLIP in malignant melanocytic skin lesions. J Invest Dermatol. 2001;117:360–364.

    CAS  PubMed  Google Scholar 

  62. Okano H, Shiraki K, Inoue H, et al. Cellular FLICE/caspase-8-inhibitory protein as a principal regulator of cell death and survival in human hepatocellular carcinoma. Lab Invest. 2003;83:1033–1043.

    CAS  PubMed  Google Scholar 

  63. Tepper CG, Seldin MF . Modulation of caspase-8 and FLICE-inhibitory protein expression as a potential mechanism of Epstein–Barr virus tumorigenesis in Burkitt's lymphoma. Blood. 1999;94:1727–1737.

    CAS  PubMed  Google Scholar 

  64. French LE, Tschopp J . Inhibition of death receptor signaling by FLICE-inhibitory protein as a mechanism for immune escape of tumors. J Exp Med. 1999;190:891–894.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Medema JP, de Jong J, van Hall T, et al. Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein. J Exp Med. 1999;190:1033–1038.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Fulda S, Meyer E, Debatin KM . Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. Oncogene. 2002;21:2283–2294.

    CAS  PubMed  Google Scholar 

  67. Kandasamy K, Srinivasula SM, Alnemri ES, et al. Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: differential regulation of cytochrome c and Smac/DIABLO release. Cancer Res. 2003;63:1712–1721.

    CAS  PubMed  Google Scholar 

  68. LeBlanc H, Lawrence D, Varfolomeev E, et al. Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med. 2002;8:274–281.

    CAS  PubMed  Google Scholar 

  69. Wang GQ, Gastman BR, Wieckowski E, et al. A role for mitochondrial Bak in apoptotic response to anticancer drugs. J Biol Chem. 2001;276:34307–34317.

    CAS  PubMed  Google Scholar 

  70. Duckett CS, Nava VE, Gedrich RW, et al. A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. EMBO J. 1996;15:2685–2694.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. McEleny KR, Watson RW, Fitzpatrick JM . Defining a role for the inhibitors of apoptosis proteins in prostate cancer. Prostate Cancer Prostatic Dis. 2001;4:28–32.

    CAS  PubMed  Google Scholar 

  72. Ng CP, Zisman A, Bonavida B . Synergy is achieved by complementation with Apo2L/TRAIL and actinomycin D in Apo2L/TRAIL-mediated apoptosis of prostate cancer cells: role of XIAP in resistance. Prostate. 2002;53:286–299.

    CAS  PubMed  Google Scholar 

  73. Ng CP, Bonavida B . X-linked inhibitor of apoptosis (XIAP) blocks Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of prostate cancer cells in the presence of mitochondrial activation: sensitization by overexpression of second mitochondria-derived activator of caspase/direct IAP-binding protein with low pl (Smac/DIABLO). Mol Cancer Ther. 2002;1:1051–1058.

    CAS  PubMed  Google Scholar 

  74. Du C, Fang M, Li Y, et al. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:33–42.

    CAS  PubMed  Google Scholar 

  75. Verhagen AM, Ekert PG, Pakusch M, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000;102:43–53.

    CAS  PubMed  Google Scholar 

  76. Zhang XD, Zhang XY, Gray CP, et al. Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of human melanoma is regulated by smac/DIABLO release from mitochondria. Cancer Res. 2001;61:7339–7348.

    CAS  PubMed  Google Scholar 

  77. Bernard D, Quatannens B, Vandenbunder B, et al. Rel/NF-kappaB transcription factors protect against tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by up-regulating the TRAIL decoy receptor DcR1. J Biol Chem. 2001;276:27322–27328.

    CAS  PubMed  Google Scholar 

  78. Harper N, Farrow SN, Kaptein A, et al. Modulation of tumor necrosis factor apoptosis-inducing ligand-induced NF-kappa B activation by inhibition of apical caspases. J Biol Chem. 2001;276:34743–34752.

    CAS  PubMed  Google Scholar 

  79. Kim YS, Schwabe RF, Qian T, et al. TRAIL-mediated apoptosis requires NF-kappaB inhibition and the mitochondrial permeability transition in human hepatoma cells. Hepatology. 2002;36:1498–1508.

    CAS  PubMed  Google Scholar 

  80. Ehrhardt H, Fulda S, Schmid I, et al. TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB. Oncogene. 2003;22:3842–3852.

    CAS  PubMed  Google Scholar 

  81. Shetty S, Gladden JB, Henson ES, et al. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) up-regulates death receptor 5 (DR5) mediated by NFkappaB activation in epithelial derived cell lines. Apoptosis. 2002;7:413–420.

    CAS  PubMed  Google Scholar 

  82. Chen X, Kandasamy K, Srivastava RK . Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B in tumor necrosis factor-related apoptosis-inducing ligand signaling. Cancer Res. 2003;63:1059–1066.

    CAS  PubMed  Google Scholar 

  83. Ichijo H . From receptors to stress-activated MAP kinases. Oncogene. 1999;18:6087–6093.

    CAS  PubMed  Google Scholar 

  84. Zhang XD, Borrow JM, Zhang XY, et al. Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene. 2003;22:2869–2881.

    CAS  PubMed  Google Scholar 

  85. Frese S, Pirnia F, Miescher D, et al. PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2. Oncogene. 2003;22:5427–5435.

    CAS  PubMed  Google Scholar 

  86. Ohtsuka T, Buchsbaum D, Oliver P, et al. Synergistic induction of tumor cell apoptosis by death receptor antibody and chemotherapy agent through JNK/p38 and mitochondrial death pathway. Oncogene. 2003;22:2034–2044.

    CAS  PubMed  Google Scholar 

  87. Sah NK, Munshi A, Kurland JF, et al. Translation inhibitors sensitize prostate cancer cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by activating c-Jun N-terminal kinase. J Biol Chem. 2003;278:20593–20602.

    CAS  PubMed  Google Scholar 

  88. Zhang L, Zhu H, Davis JJ, et al. Lack of p38 MAP kinase activation in TRAIL-resistant cells is not related to the resistance to TRAIL-mediated cell death. Cancer Biol Ther. 2004;3:296–301.

    CAS  PubMed  Google Scholar 

  89. Ono K, Han J . The p38 signal transduction pathway: activation and function. Cell Signal. 2000;12:1–13.

    CAS  PubMed  Google Scholar 

  90. Shankar S, Srivastava RK . Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications. Drug Resist Updat. 2004;7:139–156.

    CAS  PubMed  Google Scholar 

  91. Ichikawa K, Liu W, Zhao L, et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med. 2001;7:954–960.

    CAS  PubMed  Google Scholar 

  92. Wang Y, Engels IH, Knee DA, et al. Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. Cancer Cell. 2004;5:501–512.

    CAS  PubMed  Google Scholar 

  93. Lawrence D, Shahrokh Z, Marsters S, et al. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med. 2001;7:383–385.

    CAS  PubMed  Google Scholar 

  94. Jo M, Kim TH, Seol DW, et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med. 2000;6:564–567.

    CAS  PubMed  Google Scholar 

  95. Zhang XD, Nguyen T, Thomas WD, et al. Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types. FEBS Lett. 2000;482:193–199.

    CAS  PubMed  Google Scholar 

  96. Bhojani MS, Rossu BD, Rehemtulla A . TRAIL and anti-tumor responses. Cancer Biol Ther. 2003;2:S71–S78.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Christine Wogan for editorial review.

Author information

Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Lidong Zhang & Bingliang Fang

Authors
  1. Lidong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bingliang Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bingliang Fang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, L., Fang, B. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther 12, 228–237 (2005). https://doi.org/10.1038/sj.cgt.7700792

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700792

Keywords

This article is cited by

Search

Advanced search

Quick links