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Death Signaling and Therapeutic Applications of TRAIL

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Death Receptors in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Apoptosis is a biological process that plays a pivotal role in the development and homeostasis of multicellular organisms (1–3). Aberrations of this process can be detrimental to organisms. Excessive apoptosis causes damage to normal tissues in certain autoimmune disorders; however, a failure of apoptosis allows cells to grow unlimitedly, resulting in neoplasia. A wide variety of molecules have been identified to induce apoptosis. Among these molecules, ligand-type cytokine molecules including the tumor necrosis factor (TNF) family members have been best characterized. The TNF family members most extensively characterized for death signaling and structure include TNF-α, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL).

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References

  1. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998;281:1305–1308.

    Article  PubMed  CAS  Google Scholar 

  2. Nagata S. Apoptosis by death factor. Cell 1997;88:355–3365.

    Article  PubMed  CAS  Google Scholar 

  3. Salvesen GS, Dixit VM. Caspases: intracellular signaling by proteolysis. Cell 1997;91:443–446.

    Article  PubMed  CAS  Google Scholar 

  4. Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995;3:673–682.

    Article  PubMed  CAS  Google Scholar 

  5. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996;271:12,687–12,690.

    Article  PubMed  CAS  Google Scholar 

  6. Liabakk NB, Sundan A, Torp S, Aukrust P, Froland SS, Espevik T. Development, characterization and use of monoclonal antibodies against sTRAIL: measurement of sTRAIL by ELISA. J Immunol Methods 2002;259:119–128.

    Article  PubMed  CAS  Google Scholar 

  7. Cha SS, Kim MS, Choi YH, et al. 2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity. Immunity 1999;11:253–261.

    Article  PubMed  CAS  Google Scholar 

  8. Hymowitz SG, Christinger HW, Fuh G, et al. Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol Cell 1999;4:563–571.

    Article  PubMed  CAS  Google Scholar 

  9. Hymowitz SG, O’Connell MP, Ultsch MH, et al. A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL. Biochemistry 2000;39:633–640.

    Article  PubMed  CAS  Google Scholar 

  10. Seol DW, Billiar TR. Cysteine 230 modulates tumor necrosis factor-related apoptosis-inducing ligand activity. Cancer Res 2000;60:3152–3154.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 1997;277:815–818.

    Article  PubMed  CAS  Google Scholar 

  13. 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.

    Article  PubMed  CAS  Google Scholar 

  14. MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. J Biol Chem 1997;272:25,417–25,420.

    Article  PubMed  CAS  Google Scholar 

  15. Mongkolsapaya J, Cowper AE, Xu XN, et al. Lymphocyte inhibitor of TRAIL (TNF-related apoptosis-inducing ligand): a new receptor protecting lymphocytes from the death ligand TRAIL. J Immunol 1998;160:3–6.

    PubMed  CAS  Google Scholar 

  16. 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.

    Article  PubMed  CAS  Google Scholar 

  17. Pan G, Ni J, Yu G, Wei YF, Dixit VM. TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling. FEBS Lett 1998;424:41–45.

    Article  PubMed  CAS  Google Scholar 

  18. Marsters SA, Sheridan JP, Pitti RM, et al. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol 1997;7:1003–1006.

    Article  PubMed  CAS  Google Scholar 

  19. Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG. 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  PubMed  CAS  Google Scholar 

  20. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998;273:14363–4367.

    Article  PubMed  CAS  Google Scholar 

  21. Truneh A, Sharma S, Silverman C, et al. Temperature-sensitive differential affinity of TRAIL for its receptors. DR5 is the highest affinity receptor. J Biol Chem 2000;275:23,319–23,325.

    Article  PubMed  CAS  Google Scholar 

  22. Ashkenazi A, Pai RC, Fong S, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999;104:155–162.

    Article  PubMed  CAS  Google Scholar 

  23. Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999;5:157–163.

    Article  PubMed  CAS  Google Scholar 

  24. Kelley SK, Harris LA, Xie D, et al. Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety. J Pharmacol Exp Ther 2001;299:31–38.

    PubMed  CAS  Google Scholar 

  25. Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al. Lethal effect of the anti-Fas antibody in mice. Nature 1993;364:806–809.

    Article  PubMed  CAS  Google Scholar 

  26. Galle PR, Hofmann WJ, Walczak H, et al. Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med 1995;182:1223–1230.

    Article  PubMed  CAS  Google Scholar 

  27. Jeremias I, Herr I, Boehler T, Debatin KM. TRAIL/Apo-2-ligand-induced apoptosis in human T cells. Eur J Immunol 1998;28:143–152.

    Article  PubMed  CAS  Google Scholar 

  28. Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 2002;168:1356–1361.

    PubMed  CAS  Google Scholar 

  29. Lamhamedi-Cherradi SE, Zheng SJ, Maguschak KA, Peschon J, Chen YH. Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL(−/−) mice. Nat Immunol 2003;4:255–260.

    Article  PubMed  CAS  Google Scholar 

  30. Takeda K, Smyth MJ, Cretney E, et al. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 2002;195:161–169.

    Article  PubMed  CAS  Google Scholar 

  31. Sprick MR, Weigand MA, Rieser E, et al. FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 2000;12:599–609.

    Article  PubMed  CAS  Google Scholar 

  32. Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 2000;12:611–620.

    Article  PubMed  CAS  Google Scholar 

  33. Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997;91:479–489.

    Article  PubMed  CAS  Google Scholar 

  34. Miyazaki T, Reed JC. A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteins. Nat Immunol 2001;2:493–500.

    Article  PubMed  CAS  Google Scholar 

  35. Berger T, Kretzler M. Interaction of DAP3 and FADD only after cellular disruption. Nat Immunol 2002;3:3–5.

    Article  PubMed  CAS  Google Scholar 

  36. Berger T, Kretzler M. TRAIL-induced apoptosis is independent of the mitochondrial apoptosis mediator DAP3. Biochem Biophys Res Commun 2002;297:880–884.

    Article  PubMed  CAS  Google Scholar 

  37. Sprick MR, Rieser E, Stahl H, Grosse-Wilde A, Weigand MA, Walczak H. 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.

    Article  PubMed  CAS  Google Scholar 

  38. 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;276:46,639–46,646.

    Article  PubMed  CAS  Google Scholar 

  39. Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM. An induced proximity model for caspase-8 activation. J Biol Chem 1998;273:2926–2930.

    Article  PubMed  CAS  Google Scholar 

  40. Salvesen GS, Dixit VM. Caspase activation: the induced-proximity model. Proc Natl Acad Sci USA 1999;96:10,964–10,967.

    Article  PubMed  CAS  Google Scholar 

  41. Seol DW, Li J, Seol MH, Park SY, Talanian RV, Billiar TR. 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.

    PubMed  CAS  Google Scholar 

  42. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998;94:491–501.

    Article  PubMed  CAS  Google Scholar 

  43. Gross A, Yin XM, Wang K, et al. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem 1999;274: 1156–1163.

    Article  PubMed  CAS  Google Scholar 

  44. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998;94:481–490.

    Article  PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  47. Susin SA, Lorenzo HK, Zamzami N, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441–446.

    Article  PubMed  CAS  Google Scholar 

  48. Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 2001;412:95–99.

    Article  PubMed  CAS  Google Scholar 

  49. Susin SA, Lorenzo HK, Zamzami N, et al. Mitochondrial release of caspase-2 and-9 during the apoptotic process. J Exp Med 1999;189:381–394.

    Article  PubMed  CAS  Google Scholar 

  50. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 1998;391:43–50.

    Article  PubMed  CAS  Google Scholar 

  51. Sakahira H, Enari M, Nagata S. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 1998;391:96–99.

    Article  PubMed  CAS  Google Scholar 

  52. Liu X, Li P, Widlak P, et al. The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis. Proc Natl Acad Sci USA 1998;95:8461–8466.

    Article  PubMed  CAS  Google Scholar 

  53. Scaffidi C, Fulda S, Srinivasan A, et al. Two CD95 (APO-1/Fas) signaling pathways. Embo J 1998;17:1675–1687.

    Article  PubMed  CAS  Google Scholar 

  54. Ozoren N, El-Deiry WS. Defining characteristics of Types I and II apoptotic cells in response to TRAIL. Neoplasia 2002;4:551–557.

    Article  PubMed  CAS  Google Scholar 

  55. Zhang XD, Franco A, Myers K, Gray C, Nguyen T, Hersey P. Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res 1999; 59:2747–2753.

    PubMed  CAS  Google Scholar 

  56. Griffith TS, Rauch CT, Smolak PJ, et al. Functional analysis of TRAIL receptors using monoclonal antibodies. J Immunol 1999;162:2597–2605.

    PubMed  CAS  Google Scholar 

  57. Leverkus M, Neumann M, Mengling T, et al. Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary and transformed human keratinocytes. Cancer Res 2000;60:553–559.

    PubMed  CAS  Google Scholar 

  58. Zhang XD, Franco AV, Nguyen T, Gray CP, Hersey P. Differential localization and regulation of death and decoy receptors for TNF-related apoptosis-inducing ligand (TRAIL) in human melanoma cells. J Immunol 2000;164:3961–3970.

    PubMed  CAS  Google Scholar 

  59. 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.

    PubMed  CAS  Google Scholar 

  60. 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.

    PubMed  CAS  Google Scholar 

  61. Wu GS, Burns TF, McDonald ER, 3rd, et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 1997;17:141–143.

    Article  PubMed  CAS  Google Scholar 

  62. Sheikh MS, Burns TF, Huang Y, et al. p53-dependent and-independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor alpha. Cancer Res 1998;58:1593–1598.

    PubMed  CAS  Google Scholar 

  63. Sheikh MS, Huang Y, Fernandez-Salas EA, et al. The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. Oncogene 1999;18:4153–4159.

    Article  PubMed  CAS  Google Scholar 

  64. Meng RD, McDonald ER, 3rd, Sheikh MS, Fornace AJ, Jr., El-Deiry WS. The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis. Mol Ther 2000;1:130–144.

    Article  PubMed  CAS  Google Scholar 

  65. Kuang AA, Diehl GE, Zhang J, Winoto A. FADD is required for DR4-and DR5-mediated apoptosis: lack of TRAIL-induced apoptosis in FADD-deficient mouse embryonic fibroblasts. J Biol Chem 2000;275:25,065–25,068.

    Article  PubMed  CAS  Google Scholar 

  66. Kim IK, Chung CW, Woo HN, Hong GS, Nagata S, Jung YK. Reconstitution of caspase-8 sensitizes JB6 cells to TRAIL. Biochem Biophys Res Commun 2000;277:311–316.

    Article  PubMed  CAS  Google Scholar 

  67. 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.

    Article  PubMed  CAS  Google Scholar 

  68. Hopkins-Donaldson S, Bodmer JL, Bourloud KB, Brognara CB, Tschopp J, Gross N. Loss of caspase-8 expression in highly malignant human neuroblastoma cells correlates with resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res 2000;60:4315–4319.

    PubMed  CAS  Google Scholar 

  69. Grotzer MA, Eggert A, Zuzak TJ, et al. Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression. Oncogene 2000;19:4604–4610.

    Article  PubMed  CAS  Google Scholar 

  70. Eggert A, Grotzer MA, Zuzak TJ, Wiewrodt BR, Ikegaki N, Brodeur GM. Resistance to TRAIL-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Med Pediatr Oncol 2000;35:603–607.

    Article  PubMed  CAS  Google Scholar 

  71. 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.

    PubMed  CAS  Google Scholar 

  72. Kim Y, Suh N, Sporn M, Reed JC. An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. J Biol Chem 2002;277:22,320–22,329.

    Article  PubMed  CAS  Google Scholar 

  73. Xiao C, Yang BF, Asadi N, Beguinot F, Hao C. Tumor necrosis factor-related apoptosis-inducing ligand-induced death-inducing signaling complex and its modulation by c-FLIP and PED/PEA-15 in glioma cells. J Biol Chem 2002;277:25,020–25,025.

    Article  PubMed  CAS  Google Scholar 

  74. 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.

    Article  PubMed  CAS  Google Scholar 

  75. Olsson A, Diaz T, Aguilar-Santelises M, et al. Sensitization to TRAIL-induced apoptosis and modulation of FLICE-inhibitory protein in B chronic lymphocytic leukemia by actinomycin D. Leukemia 2001;15:1868–1877.

    PubMed  CAS  Google Scholar 

  76. Kreuz S, Siegmund D, Scheurich P, Wajant H. NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol Cell Biol 2001;21:3964–3973.

    Article  PubMed  CAS  Google Scholar 

  77. Micheau O, Lens S, Gaide O, Alevizopoulos K, Tschopp J. NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol 2001;21:5299–5305.

    Article  PubMed  CAS  Google Scholar 

  78. Wu Xiao C, Asselin E, Tsang BK. Nuclear factor kappaB-mediated induction of FLICE-like inhibitory protein prevents tumor necrosis factor alpha-induced apoptosis in rat granulosa cells. Biol Reprod 2002;67: 436–441.

    Article  Google Scholar 

  79. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231–241.

    Article  PubMed  CAS  Google Scholar 

  80. Dudek H, Datta SR, Franke TF, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 1997;275:661–665.

    Article  PubMed  CAS  Google Scholar 

  81. Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998;282:1318–1321.

    Article  PubMed  CAS  Google Scholar 

  82. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857–868.

    Article  PubMed  CAS  Google Scholar 

  83. Tang ED, Nunez G, Barr FG, Guan KL. Negative regulation of the Forkhead transcription factor FKHR by Akt. J Biol Chem 1999;274:16,741–16,746.

    Article  PubMed  CAS  Google Scholar 

  84. Kashii Y, Uchida M, Kirito K, et al. A member of Forkhead family transcription factor, FKHRL1, is one of the downstream molecules of phosphatidylinositol 3-kinase-Akt activation pathway in erythropoietin signal transduction. Blood 2000;96:941–949.

    PubMed  CAS  Google Scholar 

  85. Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M, Sellers WR. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol Cell Biol 2000;20:8969–8982.

    Article  PubMed  CAS  Google Scholar 

  86. Nesterov A, Lu X, Johnson M, Miller GJ, Ivashchenko Y, Kraft AS. Elevated AKT activity protects the prostate cancer cell line LNCaP from TRAIL-induced apoptosis. J Biol Chem 2001;276:10,767–10,774.

    Article  PubMed  CAS  Google Scholar 

  87. Chen X, Thakkar H, Tyan F, et al. Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene 2001;20:6073–6083.

    Article  PubMed  CAS  Google Scholar 

  88. Shinohara H, Kayagaki N, Yagita H, et al. A protective role of PKCepsilon against TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in glioma cells. Biochem Biophys Res Commun 2001;284:1162–1167.

    Article  PubMed  CAS  Google Scholar 

  89. Sarker M, Ruiz-Ruiz C, Lopez-Rivas A. Activation of protein kinase C inhibits TRAIL-induced caspases activation, mitochondrial events and apoptosis in a human leukemic T cell line. Cell Death Differ 2001;8:172–181.

    Article  PubMed  CAS  Google Scholar 

  90. Deng Y, Lin Y, Wu X. TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev 2002;16:33–45.

    Article  PubMed  CAS  Google Scholar 

  91. 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.

    Article  PubMed  CAS  Google Scholar 

  92. Ravi R, Bedi A. Requirement of BAX for TRAIL/Apo2L-induced apoptosis of colorectal cancers: synergism with sulindac-mediated inhibition of Bcl-x(L). Cancer Res 2002;62:1583–1587.

    PubMed  CAS  Google Scholar 

  93. He Q, Luo X, Huang Y, Sheikh MS. Apo2L/TRAIL differentially modulates the apoptotic effects of sulindac and a COX-2 selective non-steroidal anti-inflammatory agent in Bax-deficient cells. Oncogene 2002;21:6032–6040.

    Article  PubMed  CAS  Google Scholar 

  94. Wei MC, Zong WX, Cheng EH, et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 2001;292:727–730.

    Article  PubMed  CAS  Google Scholar 

  95. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 1995;80:285–291.

    Article  PubMed  CAS  Google Scholar 

  96. Lamothe B, Aggarwal BB. Ectopic expression of Bcl-2 and Bcl-xL inhibits apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) through suppression of caspases-8, 7, and 3 and BID cleavage in human acute myelogenous leukemia cell line HL-60. J Interferon Cytokine Res 2002;22:269–279.

    Article  PubMed  CAS  Google Scholar 

  97. Sun SY, Yue P, Zhou JY, et al. Overexpression of BCL2 blocks TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. Biochem Biophys Res Commun 2001;280: 788–797.

    Article  PubMed  CAS  Google Scholar 

  98. Munshi A, Pappas G, Honda T, et al. TRAIL (APO-2L) induces apoptosis in human prostate cancer cells that is inhibitable by Bcl-2. Oncogene 2001;20:3757–3765.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  100. Rokhlin OW, Guseva N, Tagiyev A, Knudson CM, Cohen MB. Bcl-2 oncoprotein protects the human prostatic carcinoma cell line PC3 from TRAIL-mediated apoptosis. Oncogene 2001;20:2836–2843.

    Article  PubMed  CAS  Google Scholar 

  101. Pugazhenthi S, Miller E, Sable C, et al. Insulin-like growth factor-I induces bcl-2 promoter through the transcription factor cAMP-response element-binding protein. J Biol Chem 1999;274:27,529–27,535.

    Article  PubMed  CAS  Google Scholar 

  102. Pugazhenthi S, Nesterova A, Sable C, et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 2000;275:10,761–10,766.

    Article  PubMed  CAS  Google Scholar 

  103. Park SY, Billiar TR, Seol DW. Hypoxia inhibition of apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Biochem Biophys Res Commun 2002;291:150–153.

    Article  PubMed  CAS  Google Scholar 

  104. Suzuki Y, Nakabayashi Y, Nakata K, Reed JC, Takahashi R. X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and-7 in distinct modes. J Biol Chem 2001;276:27,058–27,063.

    Article  PubMed  CAS  Google Scholar 

  105. Deveraux QL, Roy N, Stennicke HR, et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. Embo J 1998;17:2215–2223.

    Article  PubMed  CAS  Google Scholar 

  106. Silke J, Ekert PG, Day CL, et al. Direct inhibition of caspase 3 is dispensable for the anti-apoptotic activity of XIAP. Embo J 2001;20:3114–3123.

    Article  PubMed  CAS  Google Scholar 

  107. Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H. Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain. Cell 2001;104:781–790.

    PubMed  CAS  Google Scholar 

  108. Riedl SJ, Renatus M, Schwarzenbacher R, et al. Structural basis for the inhibition of caspase-3 by XIAP. Cell 2001;104:791–800.

    Article  PubMed  CAS  Google Scholar 

  109. Bratton SB, Walker G, Srinivasula SM, et al. Recruitment, activation and retention of caspases-9 and-3 by Apaf-1 apoptosome and associated XIAP complexes. Embo J 2001;20:998–1009.

    Article  PubMed  CAS  Google Scholar 

  110. Chai J, Shiozaki E, Srinivasula SM, et al. Structural basis of caspase-7 inhibition by XIAP. Cell 2001;104:769–780.

    Article  PubMed  CAS  Google Scholar 

  111. Liu Z, Sun C, Olejniczak ET, et al. Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature 2000;408:1004–1008.

    Article  PubMed  CAS  Google Scholar 

  112. Wu G, Chai J, Suber TL, et al. Structural basis of IAP recognition by Smac/DIABLO. Nature 2000;408:1008–1012.

    Article  PubMed  CAS  Google Scholar 

  113. Srinivasula SM, Hegde R, Saleh A, et al. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 2001;410:112–116.

    Article  PubMed  CAS  Google Scholar 

  114. Srinivasula SM, Datta P, Fan XJ, Fernandes-Alnemri T, Huang Z, Alnemri ES. Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway. J Biol Chem 2000;275:36,152–36,157.

    Article  PubMed  CAS  Google Scholar 

  115. Ekert PG, Silke J, Hawkins CJ, Verhagen AM, Vaux DL. DIABLO promotes apoptosis by removing MIHA/XIAP from processed caspase 9. J Cell Biol 2001;152:483–490.

    Article  PubMed  CAS  Google Scholar 

  116. Yang Y, Fang S, Jensen JP, Weissman AM, Ashwell JD. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 2000;288:874–877.

    Article  PubMed  CAS  Google Scholar 

  117. Suzuki Y, Nakabayashi Y, Takahashi R. Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc Natl Acad Sci USA 2001;98:8662–8667.

    Article  PubMed  CAS  Google Scholar 

  118. Fulda S, Wick W, Weller M, Debatin KM. Smac agonists sensitize for Apo2L/TRAIL-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 2002;8:808–815.

    PubMed  CAS  Google Scholar 

  119. Guo F, Nimmanapalli R, Paranawithana S, et al. Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis. Blood 2002;99:3419–3426.

    Article  PubMed  CAS  Google Scholar 

  120. Griffith TS, Anderson RD, Davidson BL, Williams RD, Ratliff TL. Adenoviral-mediated transfer of the TNF-related apoptosis-inducing ligand/Apo-2 ligand gene induces tumor cell apoptosis. J Immunol 2000;165:2886–2894.

    PubMed  CAS  Google Scholar 

  121. Lee J, Hampl M, Albert P, Fine HA. Antitumor activity and prolonged expression from a TRAIL-expressing adenoviral vector. Neoplasia 2002;4:312–323.

    Article  PubMed  CAS  Google Scholar 

  122. Voelkel-Johnson C, King DL, Norris JS. Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL. Cancer Gene Ther 2002;9:164–172.

    Article  PubMed  CAS  Google Scholar 

  123. Griffith TS, Broghammer EL. Suppression of tumor growth following intralesional therapy with TRAIL recombinant adenovirus. Mol Ther 2001;4:257–266.

    Article  PubMed  CAS  Google Scholar 

  124. Kagawa S, He C, Gu J, et al. Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. Cancer Res 2001;61:3330–3338.

    PubMed  CAS  Google Scholar 

  125. 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.

    PubMed  CAS  Google Scholar 

  126. Goldberg GS, Jin Z, Ichikawa H, et al. Global effects of anchorage on gene expression during mammary carcinoma cell growth reveal role of tumor necrosis factor-related apoptosis-inducing ligand in anoikis. Cancer Res 2001;61:1334–1337.

    PubMed  CAS  Google Scholar 

  127. Takeda K, Hayakawa Y, Smyth MJ, et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 2001;7:94–100.

    Article  PubMed  CAS  Google Scholar 

  128. Song K, Chen Y, Goke R, et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression. J Exp Med 2000;191:1095–1104.

    Article  PubMed  CAS  Google Scholar 

  129. 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.

    Article  PubMed  CAS  Google Scholar 

  130. Nitsch R, Bechmann I, Deisz RA, et al. Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 2000;356:827–828.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  132. Qin J, Chaturvedi V, Bonish B, Nickoloff BJ. Avoiding premature apoptosis of normal epidermal cells. Nat Med 2001;7:385–386.

    Article  PubMed  CAS  Google Scholar 

  133. Gliniak B, Le T. Tumor necrosis factor-related apoptosis-inducing ligand’s antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11. Cancer Res 1999;59:6153–6158.

    PubMed  CAS  Google Scholar 

  134. Wu XX, Kakehi Y, Mizutani Y, et al. Doxorubicin enhances TRAIL-induced apoptosis in prostate cancer. Int J Oncol 2002;20:949–954.

    PubMed  CAS  Google Scholar 

  135. Wu XX, Kakehi Y, Mizutani Y, et al. Enhancement of TRAIL/Apo2L-mediated apoptosis by adriamycin through inducing DR4 and DR5 in renal cell carcinoma cells. Int J Cancer 2003;104:409–417.

    Article  PubMed  CAS  Google Scholar 

  136. Guan B, Yue P, Clayman GL, Sun SY. Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene. J Cell Physiol 2001;188:98–105.

    Article  PubMed  CAS  Google Scholar 

  137. Jazirehi AR, Ng CP, Gan XH, Schiller G, Bonavida B. Adriamycin sensitizes the adriamycin-resistant 8226/Dox40 human multiple myeloma cells to Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-mediated (TRAIL) apoptosis. Clin Cancer Res 2001;7:3874–3883.

    PubMed  CAS  Google Scholar 

  138. Ahlemeyer B, Klumpp S, Krieglstein J. Release of cytochrome c into the extracellular space contributes to neuronal apoptosis induced by staurosporine. Brain Res 2002;934:107–116.

    Article  PubMed  CAS  Google Scholar 

  139. Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S. Distinct pathways for stimulation of cytochrome c release by etoposide. J Biol Chem 2000;275:32,438–32,443.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA

    Mi-Hyang Kim & Dai-Wu Seol PhD

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  1. Mi-Hyang Kim
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  1. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

  2. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

  3. Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA

    Wafik S. El-Deiry MD, PhD

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© 2005 Humana Press Inc., Totowa, NJ

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Kim, MH., Seol, DW. (2005). Death Signaling and Therapeutic Applications of TRAIL. In: El-Deiry, W.S. (eds) Death Receptors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-851-X:133

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  • DOI: https://doi.org/10.1385/1-59259-851-X:133

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-172-1

  • Online ISBN: 978-1-59259-851-9

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