Apoptosis

, Volume 9, Issue 6, pp 691–704 | Cite as

Apoptosome dysfunction in human cancer

  • K. M. Hajra
  • J. R. Liu
Article

Abstract

Apoptosis is a cell suicide mechanism that enables organisms to control cell number and eliminate cells that threaten survival. The apoptotic cascade can be triggered through two major pathways. Extracellular signals such as members of the tumor necrosis factor (TNF) family can activate the receptor-mediated extrinsic pathway. Alternatively, stress signals such as DNA damage, hypoxia, and loss of survival signals may trigger the mitochondrial intrinsic pathway. In the latter, mitochondrial damage results in cytochrome c release and formation of the apoptosome, a multimeric protein complex containing Apaf-1, cytochrome c, and caspase-9. Once bound to the apoptosome, caspase-9 is activated, and subsequently triggers a cascade of effector caspase activation and proteolysis, leading to apoptotic cell death. Recent efforts have led to the identification of multiple factors that modulate apoptosome formation and function. Alterations in the expression and/or function of these factors may contribute to the pathogenesis of cancer and resistance of tumor cells to chemotherapy or radiation. In this review we discuss how disruption of normal apoptosome formation and function may lead or contribute to tumor development and progression.

Apaf-1 apoptosis apoptosome Bcl-2 IAP 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Raff M. Cell suicide for beginners. Nature 1998; 396: 119–122.Google Scholar
  2. 2.
    Ameisen JC. On the origin, evolution, and nature of programmed cell death: A timeline of four billion years. Cell Death Differ 2002; 9: 367–393.Google Scholar
  3. 3.
    Budihardjo I, Oliver H, Lutter M, Luo X, Wang X. Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 1999; 15: 269–290.Google Scholar
  4. 4.
    Ashkenazi A, Dixit VM. Death receptors: Signaling and modulation. Science 1998; 281: 1305–1308.Google Scholar
  5. 5.
    Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell 1996; 86: 147–157.Google Scholar
  6. 6.
    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.Google Scholar
  7. 7.
    Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 1997; 90: 405–413.Google Scholar
  8. 8.
    Benedict MA, Hu Y, Inohara N, Nunez G. Expression and functional analysis of Apaf-1 isoforms. Extra WD-40 repeat is required for cytochrome c binding and regulated activation of procaspase-9. J Biol Chem 2000; 275: 8461–8468.Google Scholar
  9. 9.
    Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW. Three-dimensional structure of the apoptosome: Implications for assembly, procaspase-9 binding, and activation. Mol Cell 2002; 9: 423–432.Google Scholar
  10. 10.
    Jiang X, Wang X. Cytochrome C-Mediated Apoptosis. Annu Rev Biochem 2004; 73: 87–106.Google Scholar
  11. 11.
    Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES. Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Mol Cell 1998; 1: 949–957.Google Scholar
  12. 12.
    Shi Y. Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell 2002; 9: 459–470.Google Scholar
  13. 13.
    Thornberry NA, Lazebnik Y. Caspases: Enemies within. Science 1998; 281: 1312–1316.Google Scholar
  14. 14.
    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.Google Scholar
  15. 15.
    Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science 2002; 297: 1352–1354.Google Scholar
  16. 16.
    Kumar S, Vaux DL. Apoptosis. A cinderella caspase takes center stage. Science 2002; 297: 1290–1291.Google Scholar
  17. 17.
    McDonnell MA, Wang D, Khan SM, Vander Heiden MG, Kelekar A. Caspase-9 is activated in a cytochrome c-independent manner early during TNFalpha-induced apop-tosis in murine cells. Cell Death Differ 2003; 10: 1005–1015.Google Scholar
  18. 18.
    Cory S, Adams JM. The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer 2002; 2: 647–656.Google Scholar
  19. 19.
    Janiak F, Leber B, Andrews DW. Assembly of Bcl-2 into microsomal and outer mitochondrial membranes. J Biol Chem 1994; 269: 9842–9849.Google Scholar
  20. 20.
    Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 1997; 275: 1132–1136.Google Scholar
  21. 21.
    Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science 1997; 275: 1129–1132.Google Scholar
  22. 22.
    Moriishi K, Huang DC, Cory S, Adams JM. Bcl-2 family members do not inhibit apoptosis by binding the caspase activator Apaf-1. Proc Natl Acad Sci USA 1999; 96: 9683–9688.Google Scholar
  23. 23.
    Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev 1999; 13: 1899–1911.Google Scholar
  24. 24.
    Antonsson B, Conti F, Ciavatta A, et al. Inhibition of Bax channel-forming activity by Bcl-2. Science 1997; 277: 370–372.Google Scholar
  25. 25.
    Antonsson B, Montessuit S, Lauper S, Eskes R, Martinou JC. Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem J 2000; 345: 271–278.Google Scholar
  26. 26.
    Saito M, Korsmeyer SJ, Schlesinger PH. BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nat Cell Biol 2000; 2: 553–555.Google Scholar
  27. 27.
    Cheng EH, Wei MC, Weiler S, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX-and BAK-mediated mitochondrial apoptosis. Mol Cell 2001; 8: 705–711.Google Scholar
  28. 28.
    Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 2001; 15: 1481–1486.Google Scholar
  29. 29.
    Lindsten T, Ross AJ, King A, et al. The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 2000; 6: 1389–1399.Google Scholar
  30. 30.
    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.Google Scholar
  31. 31.
    del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 1997; 278: 687–689.Google Scholar
  32. 32.
    Danial NN, Gramm CF, Scorrano L, et al. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 2003; 424: 952–956.Google Scholar
  33. 33.
    Ferguson HA, Marietta PM, Van Den Berg CL. UV-induced apoptosis is mediated independent of caspase-9 in MCF-7 cells: A model for cytochrome c resistance. J Biol Chem 2003; 278: 45793–45800.Google Scholar
  34. 34.
    Beere HM, Green DR. Stress management—heat shock protein-70 and the regulation of apoptosis. Trends Cell Biol 2001; 11: 6–10.Google Scholar
  35. 35.
    Beere HM, Wolf BB, Cain K, et al. Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2000; 2: 469–475.Google Scholar
  36. 36.
    Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES. Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2000; 2: 476–483.Google Scholar
  37. 37.
    Ravagnan L, Gurbuxani S, Susin SA, et al. Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 2001; 3: 839–843.Google Scholar
  38. 38.
    Susin SA, Lorenzo HK, Zamzami N, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999; 397: 441–446.Google Scholar
  39. 39.
    Pandey P, Saleh A, Nakazawa A, et al. Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. Embo J 2000; 19: 4310–4322.Google Scholar
  40. 40.
    Bruey JM, Ducasse C, Bonniaud P, et al. Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol 2000; 2: 645–652.Google Scholar
  41. 41.
    Concannon CG, Orrenius S, Samali A. Hsp27 inhibits cytochrome c-mediated caspase activation by sequestering both pro-caspase-3 and cytochrome c. Gene Expr 2001; 9: 195–201.Google Scholar
  42. 42.
    Hughes FM, Jr., Bortner CD, Purdy GD, Cidlowski JA. Intracellular K suppresses the activation of apoptosis in lymphocytes. J Biol Chem 1997; 272: 30567–30576.Google Scholar
  43. 43.
    Cain K, Langlais C, Sun XM, Brown DG, Cohen GM. Physiological concentrations of K inhibit cytochrome c-dependent formation of the apoptosome. J Biol Chem 2001; 276: 41985–41990.Google Scholar
  44. 44.
    Jiang X, Kim HE, Shu H, et al. Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory path-way. Science 2003; 299: 223–226.Google Scholar
  45. 45.
    Magdalena C, Dominguez F, Loidi L, Puente JL. Tumour prothymosin alpha content, a potential prognostic marker for primary breast cancer. Br J Cancer 2000; 82: 584–590.Google Scholar
  46. 46.
    Orre RS, Cotter MA, 2nd, Subramanian C, Robertson ES. Prothymosin alpha functions as a cellular oncoprotein by inducing transformation of rodent fibroblasts in vitro. J Biol Chem 2001; 276: 1794–1799.Google Scholar
  47. 47.
    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.Google Scholar
  48. 48.
    Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS, Reed JC. Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. Embo J 1999; 18: 5242–5251.Google Scholar
  49. 49.
    Deveraux QL, Reed JC. IAP family proteins–suppressors of apoptosis. Genes Dev 1999; 13: 239–252.Google Scholar
  50. 50.
    Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 1997; 388: 300–304.Google Scholar
  51. 51.
    Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. Embo J 1997; 16: 6914–6925.Google Scholar
  52. 52.
    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.Google Scholar
  53. 53.
    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.Google Scholar
  54. 54.
    Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 2001; 8: 613–621.Google Scholar
  55. 55.
    Hegde R, Srinivasula SM, Zhang Z, et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 2002; 277: 432–438.Google Scholar
  56. 56.
    Martins LM, Iaccarino I, Tenev T, et al. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem 2002; 277: 439–444.Google Scholar
  57. 57.
    van Loo G, van Gurp M, Depuydt B, et al. The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ 2002; 9: 20–26.Google Scholar
  58. 58.
    Verhagen AM, Silke J, Ekert PG, et al. HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J Biol Chem 2002; 277: 445–454.Google Scholar
  59. 59.
    Suzuki Y, Takahashi-Niki K, Akagi T, Hashikawa T, Takahashi R. Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways. Cell Death Differ 2004; 11: 208–216.Google Scholar
  60. 60.
    Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282: 1318–1321.Google Scholar
  61. 61.
    Chen TH, Brody JR, Romantsev FE, et al. Structure of pp32, an acidic nuclear protein which inhibits oncogene-induced formation of transformed foci. Mol Biol Cell 1996; 7: 2045–2056.Google Scholar
  62. 62.
    Bai J, Brody JR, Kadkol SS, Pasternack GR. Tumor suppression and potentiation by manipulation of pp32 expression. Oncogene 2001; 20: 2153–2160.Google Scholar
  63. 63.
    Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 1984; 226: 1097–1099.Google Scholar
  64. 64.
    Strasser A, Harris AW, Bath ML, Cory S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 1990; 348: 331–333.Google Scholar
  65. 65.
    Reed JC, Miyashita T, Takayama S, et al. BCL-2 family proteins: Regulators of cell death involved in the pathogenesis of cancer and resistance to therapy. J Cell Biochem 1996; 60: 23–32.Google Scholar
  66. 66.
    Olopade OI, Adeyanju MO, Safa AR, et al. Overexpression of BCL-x protein in primary breast cancer is associated with high tumor grade and nodal metastases. Cancer J Sci Am 1997; 3: 230–237.Google Scholar
  67. 67.
    Friess H, Lu Z, Andren-Sandberg A, et al. Moderate activation of the apoptosis inhibitor bcl-xL worsens the prognosis in pancreatic cancer. Ann Surg 1998; 228: 780–787.Google Scholar
  68. 68.
    Marone M, Scambia G, Mozzetti S, et al. bcl-2, bax, bcl-XL, and bcl-XS expression in normal and neoplastic ovarian tissues. Clin Cancer Res 1998; 4: 517–524.Google Scholar
  69. 69.
    Biroccio A, Benassi B, D'Agnano I, et al. c-Myb and Bcl-x overexpression predicts poor prognosis in colorectal cancer: Clinical and experimental findings. Am J Pathol 2001; 158: 1289–1299.Google Scholar
  70. 70.
    Rubio N, Espana L, Fernandez Y, Blanco J, Sierra A. Metastatic behavior of human breast carcinomas overexpressing the Bcl-x(L) gene: A role in dormancy and organospecificity. Lab Invest 2001; 81: 725–734.Google Scholar
  71. 71.
    Takayama T, Nagao M, Sawada H, et al. Bcl-X expression in esophageal squamous cell carcinoma: Association with tumor progression and prognosis. J Surg Oncol 2001; 78: 116–123.Google Scholar
  72. 72.
    Yin C, Knudson CM, Korsmeyer SJ, Van Dyke T. Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 1997; 385: 637–640.Google Scholar
  73. 73.
    Rampino N, Yamamoto H, Ionov Y, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatel-lite mutator phenotype. Science 1997; 275: 967–969.Google Scholar
  74. 74.
    Meijerink JP, Mensink EJ, Wang K, et al. Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood 1998; 91: 2991–2997.Google Scholar
  75. 75.
    Ionov Y, Yamamoto H, Krajewski S, Reed JC, Perucho M. Mutational inactivation of the proapoptotic gene BAXconfers selective advantage during tumor clonal evolution. Proc Natl Acad Sci USA 2000; 97: 10872–10877.Google Scholar
  76. 76.
    Kondo S, Shinomura Y, Miyazaki Y, et al. Mutations of the bak gene in human gastric and colorectal cancers. Cancer Res 2000; 60: 4328–4330.Google Scholar
  77. 77.
    Soengas MS, Capodieci P, Polsky D, et al. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 2001; 409: 207–211.Google Scholar
  78. 78.
    Baldi A, Santini D, Russo P, et al. Analysis of APAF-1 expression in human cutaneous melanoma progression. Exp Dermatol 2004; 13: 93–97.Google Scholar
  79. 79.
    Fujimoto A, Takeuchi H, Taback B, et al. Allelic imbalance of 12q22–23 associated with APAF-1 locus correlates with poor disease outcome in cutaneous melanoma. Cancer Res 2004; 64: 2245–2250.Google Scholar
  80. 80.
    Watanabe T, Hirota Y, Arakawa Y, et al. Frequent LOH at chromosome 12q22–23 and Apaf-1 inactivation in glioblastoma. Brain Pathol 2003; 13: 431–439.Google Scholar
  81. 81.
    Jia L, Srinivasula SM, Liu FT, et al. Apaf-1 protein deficiency confers resistance to cytochrome c-dependent apoptosis in human leukemic cells. Blood 2001; 98: 414–421.Google Scholar
  82. 82.
    Wolf BB, Schuler M, Li W, et al. Defective cytochrome c-dependent caspase activation in ovarian cancer cell lines due to diminished or absent apoptotic protease activating factor-1 activity. J Biol Chem 2001; 276: 34244–34251.Google Scholar
  83. 83.
    Liu JR, Opipari AW, Tan L, et al. Dysfunctional apoptosome activation in ovarian cancer: Implications for chemoresistance. Cancer Res 2002; 62: 924–931.Google Scholar
  84. 84.
    Jolly C, Morimoto RI. Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst 2000; 92: 1564–1572.Google Scholar
  85. 85.
    Ciocca DR, Clark GM, Tandon AK, Fuqua SA, Welch WJ, McGuire WL. Heat shock protein hsp70 in patients with axillary lymph node-negative breast cancer: Prognostic implications. J Natl Cancer Inst 1993; 85: 570–574.Google Scholar
  86. 86.
    Vargas-Roig LM, Gago FE, Tello O, Aznar JC, Ciocca DR. Heat shock protein expression and drug resistance in breast cancer patients treated with induction chemotherapy. Int J Cancer 1998; 79: 468–475.Google Scholar
  87. 87.
    Wei YQ, Zhao X, Kariya Y, Teshigawara K, Uchida A. Inhibition of proliferation and induction of apoptosis by abrogation of heat-shock protein (HSP) 70 expression in tumor cells. Cancer Immunol Immunother 1995; 40: 73–78.Google Scholar
  88. 88.
    Sasaki H, Nonaka M, Fujii Y, et al. Expression of the prothymosin-a gene as a prognostic factor in lung cancer. Surg Today 2001; 31: 936–938.Google Scholar
  89. 89.
    Wu CG, Habib NA, Mitry RR, Reitsma PH, van Deventer SJ, Chamuleau RA. Overexpression of hepatic prothymosin alpha, a novel marker for human hepatocellular carcinoma. Br J Cancer 1997; 76: 1199–1204.Google Scholar
  90. 90.
    Mori M, Barnard GF, Staniunas RJ, Jessup JM, Steele GD, Jr., Chen LB. Prothymosin-alpha mRNAexpression correlates with that of c-myc in human colon cancer. Oncogene 1993; 8: 2821–2826.Google Scholar
  91. 91.
    Gaubatz S, Meichle A, Eilers M. An E-box element localized in the first intron mediates regulation of the prothymosin alpha gene by c-myc. Mol Cell Biol 1994; 14: 3853–3862.Google Scholar
  92. 92.
    Desbarats L, Gaubatz S, Eilers M. Discrimination between different E-box-binding proteins at an endogenous target gene of c-myc. Genes Dev 1996; 10: 447–460.Google Scholar
  93. 93.
    Datta SR, Brunet A, Greenberg ME. Cellular survival: A play in three Akts. Genes Dev 1999; 13: 2905–2927.Google Scholar
  94. 94.
    Bellacosa A, de Feo D, Godwin AK, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 1995; 64: 280–285.Google Scholar
  95. 95.
    Ringel MD, Hayre N, Saito J, et al. Overexpression and over-activation of Akt in thyroid carcinoma. Cancer Res 2001; 61: 6105–6111.Google Scholar
  96. 96.
    Sun M, Wang G, Paciga JE, et al. AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol 2001; 159: 431–437.Google Scholar
  97. 97.
    Schlieman MG, Fahy BN, Ramsamooj R, Beckett L, Bold RJ. Incidence, mechanism and prognostic value of activated AKT in pancreas cancer. Br J Cancer 2003; 89: 2110–2115.Google Scholar
  98. 98.
    Stal O, Perez-Tenorio G, Akerberg L, et al. Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res 2003; 5: R37–44.Google Scholar
  99. 99.
    Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997; 3: 917–921.Google Scholar
  100. 100.
    Ambrosini G, Adida C, Sirugo G, Altieri DC. Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J Biol Chem 1998; 273: 11177–11182.Google Scholar
  101. 101.
    Adams RR, Carmena M, Earnshaw WC. Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol 2001; 11: 49–54.Google Scholar
  102. 102.
    Banks DP, Plescia J, Altieri DC, et al. Survivin does not inhibit caspase-3 activity. Blood 2000; 96: 4002–4003.Google Scholar
  103. 103.
    Tamm I, Kornblau SM, Segall H, et al. Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res 2000; 6: 1796–1803.Google Scholar
  104. 104.
    Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM. ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol 2000; 10: 1359–1366.Google Scholar
  105. 105.
    Kasof GM, Gomes BC. Livin, a novel inhibitor of apoptosis protein family member. J Biol Chem 2001; 276: 3238–3246.Google Scholar
  106. 106.
    Kaufmann SH, Vaux DL. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 2003; 22: 7414–7430.Google Scholar
  107. 107.
    Reed JC. Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. Curr Opin Oncol 1995; 7: 541–546.Google Scholar
  108. 108.
    Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol 1999; 17: 2941–2953.Google Scholar
  109. 109.
    Miyashita T, Reed JC. bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNAfragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res 1992; 52: 5407–5411.Google Scholar
  110. 110.
    Kamarajan P, Sun NK, Sun CL, Chao CC. Apaf-1 over-expression partially overcomes apoptotic resistance in a cisplatin-selected HeLa cell line. FEBS Lett 2001; 505: 206–212.Google Scholar
  111. 111.
    Ogawa T, Shiga K, Hashimoto S, Kobayashi T, Horii A, Furukawa T. APAF-1-ALT, a novel alternative splicing form of APAF-1, potentially causes impeded ability of undergoing DNA damage-induced apoptosis in the LNCaP human prostate cancer cell line. Biochem Biophys Res Commun 2003; 306: 537–543.Google Scholar
  112. 112.
    Page C, Lin HJ, Jin Y, et al. Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. Anticancer Res 2000; 20: 407–416.Google Scholar
  113. 113.
    Fraser M, Leung BM, Yan X, Dan HC, Cheng JQ, Tsang BK. p53 is a determinant of X-linked inhibitor of apoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells. Cancer Res 2003; 63: 7081–7088.Google Scholar
  114. 114.
    Yuan ZQ, Feldman RI, Sussman GE, Coppola D, Nicosia SV, Cheng JQ. AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: Implication of AKT2 in chemoresistance. J Biol Chem 2003; 278: 23432–23440.Google Scholar
  115. 115.
    Knuefermann C, Lu Y, Liu B, et al. HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 2003; 22: 3205–3212.Google Scholar
  116. 116.
    Sasaki H, Sheng Y, Kotsuji F, Tsang BK. Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells. Cancer Res 2000; 60: 5659–5666.Google Scholar
  117. 117.
    Liston P, Roy N, Tamai K, et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 1996; 379: 349–353.Google Scholar
  118. 118.
    Asselin E, Mills GB, Tsang BK. XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. Cancer Res 2001; 61: 1862–1868.Google Scholar
  119. 119.
    Reed JC. Apoptosis-targeted therapies for cancer. Cancer Cell 2003; 3: 17–22.Google Scholar
  120. 120.
    Amundson SA, Myers TG, Scudiero D, Kitada S, Reed JC, Fornace AJ, Jr. An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res 2000; 60: 6101–6110.Google Scholar
  121. 121.
    Cotter FE. Antisense therapy of hematologic malignancies. Semin Hematol 1999; 36: 9–14.Google Scholar
  122. 122.
    Nahta R, Esteva FJ. Bcl-2 antisense oligonucleotides: A potential novel strategy for the treatment of breast cancer. Semin Oncol 2003; 30: 143–149.Google Scholar
  123. 123.
    Ealovega MW, McGinnis PK, Sumantran VN, Clarke MF, Wicha MS. bcl-xs gene therapy induces apoptosis of human mammary tumors in nude mice. Cancer Res 1996; 56: 1965–1969.Google Scholar
  124. 124.
    Ayash LJ, Clarke M, Adams P, et al. Clinical protocol. Purging of autologous stem cell sources with bcl-x(s) adenovirus for women undergoing high-dose chemotherapy for stage IV breast carcinoma. Hum Gene Ther 2001; 12: 2023–2025.Google Scholar
  125. 125.
    Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002; 2: 183–192.Google Scholar
  126. 126.
    Enyedy IJ, Ling Y, Nacro K, et al. Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening. J Med Chem 2001; 44: 4313–4324.Google Scholar
  127. 127.
    Luo J, Manning BD, Cantley LC. Targeting the PI3K-Akt pathway in human cancer: Rationale and promise. Cancer Cell 2003; 4: 257–262.Google Scholar
  128. 128.
    Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2003; 2: 1093–1103.Google Scholar
  129. 129.
    De Siervi A, Marinissen M, Diggs J, Wang XF, Pages G, Senderowicz A. Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: Role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1. Cancer Res 2004; 64: 743–750.Google Scholar
  130. 130.
    Hu Y, Qiao L, Wang S, et al. 3-(Hydroxymethyl)-bearing phosphatidylinositol ether lipid analogues and carbonate surrogates block PI3-K, Akt, and cancer cell growth. J Med Chem 2000; 43: 3045–3051.Google Scholar
  131. 131.
    Kozikowski AP, Sun H, Brognard J, Dennis PA. Novel PI analogues selectively block activation of the pro-survival serine/ threonine kinase Akt. J AmChem Soc 2003; 125: 1144–1145.Google Scholar
  132. 132.
    Chun KH, Kosmeder JW, 2nd, Sun S, et al. Effects of deguelin on the phosphatidylinositol 3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells. J Natl Cancer Inst 2003; 95: 291–302.Google Scholar
  133. 133.
    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.Google Scholar
  134. 134.
    Yang L, Mashima T, Sato S, et al. Predominant suppression of apoptosome by inhibitor of apoptosis protein in non-small cell lung cancer H460 cells: Therapeutic effect of a novel polyarginine-conjugated Smac peptide. Cancer Res 2003; 63: 831–837.Google Scholar
  135. 135.
    Schimmer AD, Welsh K, Pinilla C, et al. Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell 2004; 5: 25–35.Google Scholar
  136. 136.
    Huang Y, Lu M, Wu H. Antagonizing XIAP-mediated caspase-3 inhibition. Achilles' heel of cancers? Cancer Cell 2004; 5: 1–2.Google Scholar
  137. 137.
    Yang L, Cao Z, Yan H, Wood WC. Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: Implication for cancer specific therapy. Cancer Res 2003; 63: 6815–6824.Google Scholar
  138. 138.
    Blanc-Brude OP, Mesri M, Wall NR, Plescia J, Dohi T, Altieri DC. Therapeutic targeting of the survivin pathway in cancer: Initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis. Clin Cancer Res 2003; 9: 2683–2692.Google Scholar
  139. 139.
    Pisarev V, Yu B, Salup R, Sherman S, Altieri DC, Gabrilovich DI. Full-length dominant-negative survivin for cancer immunotherapy. Clin Cancer Res 2003; 9: 6523–6533.Google Scholar
  140. 140.
    Tu SP, Jiang XH, Lin MC, et al. Suppression of survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer. Cancer Res 2003; 63: 7724–7732.Google Scholar
  141. 141.
    Finkel E. The mitochondrion: Is it central to apoptosis? Science 2001; 292: 624–626.Google Scholar
  142. 142.
    Baliga B, Kumar S. Apaf-1/cytochrome c apoptosome: An essential initiator of caspase activation or just a sideshow? Cell Death Differ 2003; 10: 16–18.Google Scholar
  143. 143.
    Zheng TS, Hunot S, Kuida K, Flavell RA. Caspase knockouts: Matters of life and death. Cell Death Differ 1999; 6: 1043–1053.Google Scholar
  144. 144.
    Marsden VS, O'Connor L, O'Reilly LA, et al. Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Nature 2002; 419: 634–637.Google Scholar
  145. 145.
    Ogier-Denis E, Codogno P. Autophagy: A barrier or an adaptive response to cancer. Biochim Biophys Acta 2003; 1603: 113–128.Google Scholar
  146. 146.
    Grossman D, McNiff JM, Li F, Altieri DC. Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermatol 1999; 113: 1076–1081.Google Scholar
  147. 147.
    Chiodino C, Cesinaro AM, Ottani D, et al. Communication: Expression of the novel inhibitor of apoptosis survivin in normal and neoplastic skin. J Invest Dermatol 1999; 113: 415–418.Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • K. M. Hajra
    • 1
  • J. R. Liu
    • 1
  1. 1.Department of Obstetrics and GynecologyUniversity of Michigan Medical School, L4000 Women's HospitalAnn ArborUSA

Personalised recommendations