The promise of cancer therapeutics targeting the TNF-related apoptosis-inducing ligand and TRAIL receptor pathway

Oncogene

Volumn 27, Issue 48, 2008, Pages 6207-6215

  Wang, S ^a  

^a FUDAN UNIVERSITY   (China)

Author keywords

Apoptosis; Cancer therapy; DR4; KILLER DR5; TNF receptor superfamily; Tumor necrosis factor related apoptosis inducing ligand

Indexed keywords

1 [5 HYDROXY 2 (2 THIENYL) 4 QUINAZOLINYLAMINO] 3 METHYL 2,5 PYRROLEDIONE; 6 CHLORO 8 NICOTINAMIDO BETA CARBOLINE; ANTINEOPLASTIC AGENT; APOMAB; BH 31 2'; DEATH RECEPTOR 4; DEATH RECEPTOR 5; HISTONE DEACETYLASE INHIBITOR; MAPATUMUMAB; MONOCLONAL ANTIBODY; NOCODAZOLE; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN BCL 2; PROTEIN INHIBITOR; PROTEIN KINASE B; PROTEIN P53; RAPAMYCIN; SORAFENIB; TANESPIMYCIN; TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND; TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND RECEPTOR; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER CELL; CANCER CHEMOTHERAPY; CANCER COMBINATION CHEMOTHERAPY; CANCER RADIOTHERAPY; CANCER RESISTANCE; CLINICAL TRIAL; COLON TUMOR; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG POTENTIATION; DRUG SAFETY; DRUG SENSITIVITY; DRUG STRUCTURE; DRUG TARGETING; GENE DELETION; GENE MUTATION; HUMAN; INNATE IMMUNITY; LUNG NON SMALL CELL CANCER; LUNG TUMOR; NEOPLASM; NONHODGKIN LYMPHOMA; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN FAMILY; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; UNSPECIFIED SIDE EFFECT;

ANTINEOPLASTIC AGENTS; APOPTOSIS; HUMANS; NEOPLASMS; RECEPTORS, TNF-RELATED APOPTOSIS-INDUCING LIGAND; TNF-RELATED APOPTOSIS-INDUCING LIGAND;

EID: 54249107246     PISSN: 09509232     EISSN: 14765594     Source Type: Journal    
DOI: 10.1038/onc.2008.298     Document Type: Review

References (92)

1. Adams C, Totpal K, Lawrence D, Marsters S, Pitti R, Yee S et al. (2008). Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5. Cell Death Differ 15: 751-761.
2. Ashkenazi A. (2002). Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2: 420-430.
3. Ashkenazi A, Herbst RS. (2008). To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest 118: 1979-1990.
4. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA et al. (1999). Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 104: 155-162.
5. Blankenstein T. (2005). The role oftumor stroma in the interaction between tumor and immune system. Curr Opin Immunol 17: 180-186.
6. Bodmer JL, Holler N, Reynard S, Vinciguerra P, Schneider P, Juo P et al. (2000). TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol 2: 241-243.
7. Burns TF, El-Deiry WS. (2001). Identification of inhibitors of TRAIL-induced death (ITIDs) in the TRAIL-sensitive colon carcinoma cell line SW480 using a genetic approach. J Biol Chem 276: 37879-37886.
8. Chawla-Sarkar M, Bae SI, Reu FJ, Jacobs BS, Lindner DJ, Borden EC. (2004). Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis. Cell Death Differ 11: 915-923.
9. Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T et al. (2001). BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 8: 705-711.
10. Clohessy JG, Zhuang J, de Boer J, Gil-Gómez G, Brady HJ. (2006). Mcl-1 interacts with truncated Bid and inhibits its induction of cytochrome c release and its role in receptor-mediated apoptosis. J Biol Chem 281: 5750-5759.
11. Corazza N, Jakob S, Schaer C, Frese S, Keogh A, Stroka D et al. (2006). TRAIL receptor-mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality. J Clin Invest 116: 2493-2499.
12. Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ. (2002). Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 168: 1356-1361.
13. Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG. (1997a). The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 7: 813-820.
14. Degli-Esposti MA, Smolak PJ, Walczak H, Waugh J, Huang CP, DuBose RF et al. (1997b). Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J Exp Med 186: 1165-1170.
15. Deng Y, Lin Y, Wu X. (2002). TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIA BLO. Genes Dev 16: 33-45.
16. Diehl GE, Yue HH, Hsieh K, Kuang AA, Ho M, Morici LA et al. (2004). TRAIL-R as a negative regulator of innate immune cell responses. Immunity 21: 877-889.
17. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C et al. (1998). Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 273: 14363-14367.
18. Finnberg N, Gruber JJ, Fei P, Rudolph D, Bric A, Kim SH et al. (2005). DR5 knockout mice are compromised in radiation-induced apoptosis. Mol Cell Biol 25: 2000-2013.
19. Finnberg N, Klein-Szanto AJ, El-Deiry WS. (2008). TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis. J Clin Invest 118: 111-123.
20. Fulda S, Wick W, Weller M, Debatin KM. (2002). Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8: 808-815.
21. Georgakis GV, Li Y, Rassidakis GZ, Martinez-Valdez H, Medeiros LJ, Younes A. (2006). Inhibition ofheat shock protein 90 function by 17-allylamino-17- demethoxy-geldanamycin in Hodgkin's lymphoma cells down-regulates Akt kinase, dephosphorylates extracellular signal-regulated kinase, and induces cell cycle arrest and cell death. Clin Cancer Res 12: 584-590.
22. Gliniak B, Le T. (1999). Tumor necrosis factor-related apoptosis-inducing ligand's antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11. Cancer Res 59: 6153-6158.
23. Grosse-Wilde A, Voloshanenko O, Bailey SL, Longton GM, Schaefer U, Csernok AI et al. (2008). TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development. J Clin Invest 118: 100-110.
24. Hall MA, Cleveland JL. (2007). Clearing the TRAIL for cancer therapy. Cancer Cell 12: 4-6.
25. Hersey P, Zhang XD. (2001). How melanoma cells evade trail-induced apoptosis. Nat Rev Cancer 1: 142-150.
26. Hopkins-Donaldson S, Ziegler A, Kurtz S, Bigosch C, Kandioler D, Ludwig C et al. (2003). Silencing ofdeath receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation. Cell Death Differ 10: 356-364.
27. Hotte SJ, Hirte HW, Chen EX, Siu LL, Le LH, Corey A et al. (2008). A phase 1 study of Mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clin Cancer Res 14: 3450-3455.
28. Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O'Connell M, Kelley RF et al. (1999). Triggering cell death: the crystal structure of Apo2L/T RAIL in a complex with death receptor 5. Mol Cell 4: 563-571.
29. Jin X, Wu XX, Abdel-Muneem Nouh MA, Kakehi Y. (2007). Enhancement of death receptor 4 mediated apoptosis and cytotoxicity in renal cell carcinoma cells by subtoxic concentrations of doxorubicin. J Urol 177: 1894-1899.
30. Kaelin Jr WG. (2007). The von hippel-lindau tumor suppressor protein: an update. Methods Enzymol 435: 371-383.
31. Kataoka T. (2005). The caspase-8 modulator c-FLIP. Crit Rev Immunol 25: 31-58.
32. Khanbolooki S, Nawrocki ST, Arumugam T, Andtbacka R, Pino MS, Kurzrock R et al. (2006). Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Mol Cancer Ther 5: 2251-2260.
33. Kim M, Liao J, Dowling ML, Voong KR, Parker SE, Wang S et al. (2008a). TRAIL inactivates the mitotic checkpoint and potentiates death induced by microtubule-targeting agents in human cancer cells. Cancer Res 68: 3440-3449.
34. Kim M, Park SY, Pai HS, Kim TH, Billiar TR, Seol DW. (2004a). Hypoxia inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by blocking Bax translocation. Cancer Res 64: 4078-4081.
35. Kim SH, Kim K, Kwagh JG, Dicker DT, Herlyn M, Rustgi AK et al. (2004b). Death induction by recombinant native TRAIL and its prevention by a caspase 9 inhibitor in primary human esophageal epithelial cells. J Biol Chem 279: 40044-40052.
36. Kim SH, Ricci MS, El-Deiry WS. (2008b). Mcl-1: a gateway to TRAIL sensitization. Cancer Res 68: 2062-2064.
37. Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A. (2000). Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12: 611-620.
38. Laguinge LM, Samara RN, Wang W, El-Deiry WS, Corner G, Augenlicht L et al. (2008). DR5 receptor mediates anoikis in human colorectal carcinoma cell lines. Cancer Res 68: 909-917.
39. Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D, Mounho B et al. (2001). Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 7: 383-385.
40. LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, Schow P et al. (2002). Tumor-cell resistance to death receptor - induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med 8: 274-281.
41. Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG. (2004). A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science 305: 1471-1474.
42. Lin Y, Devin A, Cook A, Keane MM, Kelliher M, Lipkowitz S et al. (2000). The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IkappaB kinase and c-Jun N-terminal kinase. Mol Cell Biol 20: 6638-6645.
43. Liu S, Yu Y, Zhang M, Wang W, Cao X. (2001). The involvement of TNF-alpha-related apoptosis-inducing ligand in the enhanced cytotoxicity of IFN-beta-stimulated human dendritic cells to tumor cells. J Immunol 166: 5407-5415.
44. Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE et al. (1994). p53 status and the efficacy of cancer therapy in vivo. Science 266: 807-810.
45. Lowe SW, Ruley HE, Jacks T, Housman DE. (1993a). p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74: 957-967.
46. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T. (1993b). p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362: 847-849.
47. Lub-de Hooge MN, de Vries EG, de Jong S, Bijl M. (2005). Soluble TRAIL concentrations are raised in patients with systemic lupus erythematosus. Ann Rheum Dis 64: 854-858.
48. Mace TA, Yamane N, Cheng J, Hylander BL, Repasky EA. (2006). The potential of the tumor microenvironment to influence Apo2L/TRAIL induced apoptosis. Immunol Invest 35: 279-296.
49. Manning BD, Cantley LC. (2007). AKT/PKB signaling: navigating downstream. Cell 129: 1261-1274.
50. Marini P, Denzinger S, Schiller D, Kauder S, Welz S, Humphreys R et al. (2006). Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo. Oncogene 25: 5145-5154.
51. Marsters SA, Sheridan JP, Donahue CJ, Pitti RM, Gray CL, Goddard AD et al. (1996). Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-kappa B. Curr Biol 6: 1669-1676.
52. Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D et al. (1997). A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol 7: 1003-1006.
53. Meng XW, Lee SH, Dai H, Loegering D, Yu C, Flatten K et al. (2007). Mcl-1 as a buffer for proapoptotic Bcl-2 family members during TRAIL-induced apoptosis: a mechanistic basis for sorafenib (Bay 43-9006)-induced TRAIL sensitization. J Biol Chem 282: 29831-29846.
54. Mérino D, Lalaoui N, Morizot A, Schneider P, Solary E, Micheau O. (2006). Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2. Mol Cell Biol 26: 7046-7055.
55. Mongkolsapaya J, Grimes JM, Chen N, Xu XN, Stuart DI, Jones EY et al. (1999). Structure ofthe TRAIL-DR5 complex reveals mechanisms conferring specificity in apoptotic initiation. Nat Struct Biol 6: 1048-1053.
56. Ozören N, El-Deiry WS. (2002). Defining characteristics of types I and II apoptotic cells in response to TRAIL. Neoplasia 4: 551-557.
57. Ozoren N, Kim K, Burns TF, Dicker DT, Moscioni AD, El-Deiry WS. (2000). The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 60: 6259-6265.
58. Pai SI, Wu GS, Ozören N, Wu L, Jen J, Sidransky D et al. (1998). Rare loss-of-function mutation of a death receptor gene in head and neck cancer. Cancer Res 58: 3513-3518.
59. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. (1997a). An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277: 815-818.
60. Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J et al. (1997b). The receptor for the cytotoxic ligand TRAIL. Science 276: 111-113.
61. Panner A, James CD, Berger MS, Pieper RO. (2005). mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme cells. Mol Cell Biol 25: 8809-8823.
62. Pespeni MH, Hodnett M, Abayasiriwardana KS, Roux J, Howard M, Broaddus VC et al. (2007). Sensitization of mesothelioma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by heat stress via the inhibition ofthe 3-phosphoinositide-dependent kinase 1/Akt pathway. Cancer Res 67: 2865-2871.
63. Ravi R, Bedi A. (2002). Potential methods to circumvent blocks in apoptosis in lymphomas. Curr Opin Oncol 14: 490-503.
64. Ray S, Bucur O, Almasan A. (2005). Sensitization of prostate carcinoma cells to Apo2L/TRAIL by a Bcl-2 family protein inhibitor. Apoptosis 10: 1411-1418.
65. Ricci MS, Jin Z, Dews M, Yu D, Thomas-Tikhonenko A, Dicker DT et al. (2004). Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity. Mol Cell Biol 24: 8541-8555.
66. Ricci MS, Kim SH, Ogi K, Plastaras JP, Ling J, Wang W et al. (2007). Reduction of TRAIL-indu ced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. Cancer Cell 12: 66-80.
67. Romagnoli M, Desplanques G, Maïga S, Legouill S, Dreano M, Bataille R et al. (2007). Canonical nuclear factor kappaB pathway inhibition blocks myeloma cell growth and induces apoptosis in strong synergy with TRAIL. Clin Cancer Res 13: 6010-6018.
68. Rosato RR, Almenara JA, Coe S, Grant S. (2007). The multikinase inhibitor sorafenib potentiates TRAIL lethality in human leukemia cells in association with Mcl-1 and cFLIPL down-regulation. Cancer Res 67: 9490-9500.
69. Schneider P, Olson D, Tardivel A, Browning B, Lugovskoy A, Gong D et al. (2003). Identification of a new murine tumor necrosis factor receptor locus that contains two novel murine receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). J Biol Chem 278: 5444-5454.
70. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D et al. (1997). Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277: 818-821.
71. Shrader M, Pino MS, Lashinger L, Bar-Eli M, Adam L, Dinney CP et al. (2007). Gefitinib reverses TRAIL resistance in human bladder cancer cell lines via inhibition of AKT-mediated X-linked inhibitor of apoptosis protein expression. Cancer Res 67: 1430-1435.
72. Singh TR, Shankar S, Srivastava RK. (2005). HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma. Oncogene 24: 4609-4623.
73. Sinicrope FA, Penington RC, Tang XM. (2004). Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis is inhibited by Bcl-2 but restored by the small molecule Bcl-2 inhibitor, HA 14-1, in human colon cancer cells. Clin Cancer Res 10: 8284-8292.
74. Smyth MJ, Takeda K, Hayakawa Y, Peschon JJ, van den Brink MR, Yagita H. (2003). Nature's TRAIL - on a path to cancer immunotherapy. Immunity 18: 1-6.
75. Sprick MR, Weigand MA, Rieser E, Rauch CT, Juo P, Blenis J et al. (2000). FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12: 599-609.
76. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S et al. (2001). Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 7: 94-100.
77. Trauzold A, Siegmund D, Schniewind B, Sipos B, Egberts J, Zorenkov D et al. (2006). TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene 25: 7434-7439.
78. Vivanco I, Sawyers CL. (2002). The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2: 489-501.
79. Wagner KW, Punnoose EA, Januario T, Lawrence DA, Pitti RM, Lancaster K et al. (2007). Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL. Nat Med 13: 1070-1077.
80. Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N et al. (1997). TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J 16: 5386-5397.
81. Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M et al. (1999). Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 5: 157-163.
82. Wandinger KP, Lünemann JD, Wengert O, Bellmann-Strobl J, Aktas O, Weber A et al. (2003). TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Lancet 361: 2036-2043.
83. Wang S, El-Deiry WS. (2003a). Requirement of p53 targets in chemosensitization of colonic carcinoma to death ligand therapy. Proc Natl Acad Sci USA 100: 15095-15100.
84. Wang S, El-Deiry WS. (2003b). TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22: 8628-8633.
85. Wang S, El-Deiry WS. (2004). Inducible silencing of KILLER/DR5 in vivo promotes bioluminescent colon tumor xenograft growth and confers resistance to chemotherapeutic agent 5-fluorouracil. Cancer Res 64: 6666-6672.
86. Wang Y, Engels IH, Knee DA, Nasoff M, Deveraux QL, Quon KC. (2004). Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. Cancer Cell 5: 501-512.
87. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ et al. (2001). Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292: 727-730.
88. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK et al. (1995). Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3: 673-682.
89. Wu GS, Burns TF, McDonald III ER, Jiang W, Meng R, Krantz ID et al. (1997). KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 17: 141-143.
90. Wu GS, Burns TF, Zhan Y, Alnemri ES, El-Deiry WS. (1999). Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor. Cancer Res 59: 2770-2775.
91. Younes M, Georgakis GV, Rahmani M, Beer D, Younes A. (2006). Functional expression of TRAIL receptors TRAIL-R1 and TRAIL-R2 in esophageal adenocarcinoma. Eur J Cancer 42: 542-547.
92. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. (1997). Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation ofcaspase-3. Cell 90: 405-413.