Advertisement

Abnormalities of cell structures in tumors: apoptosis in tumors

  • Herman H. Cheung
  • Vinay Arora
  • Robert G. Korneluk
Part of the Experientia Supplementum book series (EXS, volume 96)

Abstract

A conceptual shift has occurred in recent years from considering cancer as simply a disease of deregulated cell proliferation to a view that incorporates the aberrant control of apoptosis into the equation. Apoptosis is an organized, genetically programmed cell death process by which multicellular organisms specifically destroy, dismantle and dispose of cells. In cancer cells, this tightly controlled process is suppressed by genetic lesions, allowing cancer cells to survive beyond their normal life span even in hostile environments that are prone to hypoxia and lack many trophic factor supports. In the last two decades, cancer researchers have made great strides in our understanding of the underlying molecular mechanism of apoptosis in chemoresistance generation and tumorigenesis. This tremendous increase in our knowledge of apoptosis in tumors has greatly impacted our perspective on carcinogenesis. Key regulators of apoptosis such as members of the Inhibitors of Apoptosis family and Bcl-2 family have been shown to play a pivotal role in allowing most cancer cells to escape apoptosis. The identification of specific targets involved in the suppression of apoptosis in cancer cells has facilitated the design and development of therapeutic strategies based on rational molecular approaches that aim to modulate apoptotic pathways. Many promising apoptosis-dependent strategies have been translated into clinical trials in the continued assessment of regimens that can effectively eradicate cancers.

Keywords

Apoptosis bcl-2 death receptors IAP mitochondria p53 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Lockshin RA, Williams CM (1964) Programmed cell death. II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths. J Insect Physiol 10: 643–649CrossRefGoogle Scholar
  2. 2.
    Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239–257PubMedGoogle Scholar
  3. 3.
    Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267: 1456–1462PubMedGoogle Scholar
  4. 4.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57–70CrossRefPubMedGoogle Scholar
  5. 5.
    Soini Y, Paakko P, Lehto VP (1998) Histopathological evaluation of apoptosis in cancer. Am J Pathol 153: 1041–1053PubMedGoogle Scholar
  6. 6.
    Tittel JN, Steller H (2000) A comparison of programmed cell death between species. Genome Biol 1: REVIEWS0003Google Scholar
  7. 7.
    Susin SA, Zamzami N, Castedo M, Daugas E, Wang HG, Geley S, Fassy F, Reed JC, Kroemer G (1997) The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-1/CD95-and ceramide-induced apoptosis. J Exp Med 186: 25–37CrossRefPubMedGoogle Scholar
  8. 8.
    Wyllie AH, Kerr JF, Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68: 251–306PubMedGoogle Scholar
  9. 9.
    Walker NI, Harmon BV, Gobe GC, Kerr JF (1988) Patterns of cell death. Methods Achiev Exp Pathol 13: 18–54PubMedGoogle Scholar
  10. 10.
    Cohen JJ (1991) Programmed cell death in the immune system. Adv Immunol 50: 55–85PubMedGoogle Scholar
  11. 11.
    Cummings MC, Winterford CM, Walker NI (1997) Apoptosis. Am J Surg Pathol 21: 88–101PubMedGoogle Scholar
  12. 12.
    Clarke PG (1990) Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol (Berl) 181: 195–213Google Scholar
  13. 13.
    Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284: 555–556CrossRefPubMedGoogle Scholar
  14. 14.
    Huettenbrenner S, Maier S, Leisser C, Polgar D, Strasser S, Grusch M, Krupitza G (2003) The evolution of cell death programs as prerequisites of multicellularity. Mutat Res 543: 235–249PubMedGoogle Scholar
  15. 15.
    Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281: 1312–1316CrossRefPubMedGoogle Scholar
  16. 16.
    Brady HJ (2003) Apoptosis and leukaemia. Br J Haematol 123: 577–585CrossRefPubMedGoogle Scholar
  17. 17.
    Talanian RV, Quinlan C, Trautz S, Hackett MC, Mankovich JA, Banach D, Ghayur T, Brady KD, Wong WW (1997) Substrate specificities of caspase family proteases. J Biol Chem 272: 9677–9682PubMedGoogle Scholar
  18. 18.
    Thornberry NA (1997) The caspase family of cysteine proteases. Br Med Bull 53: 478–490PubMedGoogle Scholar
  19. 19.
    Strasser A, O’Connor L, Dixit VM (2000) Apoptosis signaling. Annu Rev Biochem 69: 217–245CrossRefPubMedGoogle Scholar
  20. 20.
    Nachmias B, Ashhab Y, Ben-Yehuda D (2004) The inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer. Semin Cancer Biol 14: 231–243CrossRefPubMedGoogle Scholar
  21. 21.
    Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305: 626–629CrossRefPubMedGoogle Scholar
  22. 22.
    Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR (2000) The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol 2: 156–162PubMedGoogle Scholar
  23. 23.
    Cain K, Bratton SB, Langlais C, Walker G, Brown DG, Sun XM, Cohen GM (2000) Apaf-1 oligomerizes into biologically active approximately 700-kDa and inactive approximately 1.4-MDa apoptosome complexes. J Biol Chem 275: 6067–6070PubMedGoogle Scholar
  24. 24.
    Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P (2004) Toxic proteins released from mitochondria in cell death. Oncogene 23: 2861–2874CrossRefPubMedGoogle Scholar
  25. 25.
    Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T, Korsmeyer SJ (2003) BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300: 135–139CrossRefPubMedGoogle Scholar
  26. 26.
    Nakagawa T, Yuan J (2000) Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol 150: 887–894CrossRefPubMedGoogle Scholar
  27. 27.
    Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y (2002) An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem 277: 34287–34294CrossRefPubMedGoogle Scholar
  28. 28.
    Rao RV, Hermel E, Castro-Obregon S, del Rio G, Ellerby LM, Ellerby HM, Bredesen DE (2001) Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation. J Biol Chem 276: 33869–33874PubMedGoogle Scholar
  29. 29.
    Rao RV, Castro-Obregon S, Frankowski H, Schuler M, Stoka V, del Rio G, Bredesen DE, Ellerby HM (2002) Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. J Biol Chem 277: 21836–21842PubMedGoogle Scholar
  30. 30.
    Zong WX, Li C, Hatzivassiliou G, Lindsten T, Yu QC, Yuan J, Thompson CB (2003) Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol 162: 59–69CrossRefPubMedGoogle Scholar
  31. 31.
    Itoh N, Nagata S (1993) A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. J Biol Chem 268: 10932–10937PubMedGoogle Scholar
  32. 32.
    Tartaglia LA, Ayres TM, Wong GH, Goeddel DV (1993) A novel domain within the 55 kd TNF receptor signals cell death. Cell 74: 845–853CrossRefPubMedGoogle Scholar
  33. 33.
    Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D (1995) A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem 270: 7795–7798PubMedGoogle Scholar
  34. 34.
    Chinnaiyan AM, ORourke K, Tewari M, Dixit VM (1995) FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81: 505–512CrossRefPubMedGoogle Scholar
  35. 35.
    Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14: 5579–5588PubMedGoogle Scholar
  36. 36.
    Boldin MP, Goncharov TM, Goltsev YV, Wallach D (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1-and TNF receptor-induced cell death. Cell 85: 803–815CrossRefPubMedGoogle Scholar
  37. 37.
    Muzio M, Chinnaiyan AM, Kischkel FC, O’Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R et al. (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85: 817–827CrossRefPubMedGoogle Scholar
  38. 38.
    Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM (1998) An induced proximity model for caspase-8 activation. J Biol Chem 273: 2926–2930CrossRefPubMedGoogle Scholar
  39. 39.
    Stennicke HR, Jurgensmeier JM, Shin H, Deveraux Q, Wolf BB, Yang X, Zhou Q, Ellerby HM, Ellerby LM, Bredesen D et al. (1998) Pro-caspase-3 is a major physiologic target of caspase-8. J Biol Chem 273: 27084–27090CrossRefPubMedGoogle Scholar
  40. 40.
    Marsden VS, Strasser A (2003) Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more. Annu Rev Immunol 21: 71–105CrossRefPubMedGoogle Scholar
  41. 41.
    Holcik M, Gibson H, Korneluk RG (2001) XIAP: apoptotic brake and promising therapeutic target. Apoptosis 6: 253–261CrossRefPubMedGoogle Scholar
  42. 42.
    Liston P, Fong WG, Korneluk RG (2003) The inhibitors of apoptosis: there is more to life than Bcl2. Oncogene 22: 8568–8580CrossRefPubMedGoogle Scholar
  43. 43.
    Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388: 300–304PubMedGoogle Scholar
  44. 44.
    Takahashi R, Deveraux Q, Tamm I, Welsh K, Assa-Munt N, Salvesen GS, Reed JC (1998) A single BIR domain of XIAP sufficient for inhibiting caspases. J Biol Chem 273: 7787–7790PubMedGoogle Scholar
  45. 45.
    Pickart CM (2001) Ubiquitin enters the new millennium. Mol Cell 8: 499–504CrossRefPubMedGoogle Scholar
  46. 46.
    Huang H, Joazeiro CA, Bonfoco E, Kamada S, Leverson JD, Hunter T (2000) The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspases 3 and 7. J Biol Chem 275: 26661–26664PubMedGoogle Scholar
  47. 47.
    Suzuki Y, Nakabayashi Y, Takahashi R (2001) 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 98: 8662–8667PubMedGoogle Scholar
  48. 48.
    Salvesen GS, Duckett CS (2002) IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 3: 401–410CrossRefPubMedGoogle Scholar
  49. 49.
    Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW, Korneluk RG (2001) Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nat Cell Biol 3: 128–133CrossRefPubMedGoogle Scholar
  50. 50.
    Distelhorst CW, Shore GC (2004) Bcl-2 and calcium: controversy beneath the surface. Oncogene 23: 2875–2880CrossRefPubMedGoogle Scholar
  51. 51.
    Droin NM, Green DR (2004) Role of Bcl-2 family members in immunity and disease. Biochim Biophys Acta 1644: 179–188PubMedGoogle Scholar
  52. 52.
    Kirkin V, Joos S, Zornig M (2004) The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta 1644: 229–249PubMedGoogle Scholar
  53. 53.
    Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ (2000) Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 290: 1761–1765CrossRefPubMedGoogle Scholar
  54. 54.
    Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14: 2060–2071PubMedGoogle Scholar
  55. 55.
    Eskes R, Desagher S, Antonsson B, Martinou JC (2000) Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 20: 929–935PubMedGoogle Scholar
  56. 56.
    Kuwana T, Smith JJ, Muzio M, Dixit V, Newmeyer DD, Kornbluth S (1998) Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c. J Biol Chem 273: 16589–16594CrossRefPubMedGoogle Scholar
  57. 57.
    Li H., Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491–501CrossRefPubMedGoogle Scholar
  58. 58.
    Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94: 481–490CrossRefPubMedGoogle Scholar
  59. 59.
    Borner C (2003) The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol 39: 615–647CrossRefPubMedGoogle Scholar
  60. 60.
    Pinton P, Ferrari D, Rapizzi E, Di Virgilio F, Pozzan T, Rizzuto R (2001) The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J 20: 2690–2701CrossRefPubMedGoogle Scholar
  61. 61.
    Darios F, Lambeng N, Troadec JD, Michel PP, Ruberg M (2003) Ceramide increases mitochondrial free calcium levels via caspase 8 and Bid: role in initiation of cell death. J Neurochem 84: 643–654CrossRefPubMedGoogle Scholar
  62. 62.
    Boehning D, Patterson RL, Sedaghat L, Glebova NO, Kurosaki T, Snyder SH (2003) Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat Cell Biol 5: 1051–1061CrossRefPubMedGoogle Scholar
  63. 63.
    Ionov Y, Yamamoto H, Krajewski S, Reed JC, Perucho M (2000) Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc Natl Acad Sci USA 97: 10872–10877CrossRefPubMedGoogle Scholar
  64. 64.
    Reed JC (2003) Apoptosis-targeted therapies for cancer. Cancer Cell 3: 17–22CrossRefPubMedGoogle Scholar
  65. 65.
    Sjostrom J, Bergh J (2001) How apoptosis is regulated, and what goes wrong in cancer. BMJ 322: 1538–1539CrossRefPubMedGoogle Scholar
  66. 66.
    Sigal A, Rotter V (2000) Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res 60: 6788–6793PubMedGoogle Scholar
  67. 67.
    Jimenez GS, Nister M, Stommel JM, Beeche M, Barcarse EA, Zhang XQ, O’Gorman S, Wahl GM (2000) A transactivation-deficient mouse model provides insights into Trp53 regulation and function. Nat Genet 26: 37–43PubMedGoogle Scholar
  68. 68.
    Vogelstein B, Kinzler KW (1992) p53 function and dysfunction. Cell 70: 523–526CrossRefPubMedGoogle Scholar
  69. 69.
    Haupt S, Haupt Y (2004) Improving Cancer Therapy Through p53 Management. Cell Cycle 3: 912–916PubMedGoogle Scholar
  70. 70.
    Slee EA, O’Connor DJ, Lu X (2004) To die or not to die: how does p53 decide? Oncogene 23: 2809–2818PubMedGoogle Scholar
  71. 71.
    Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387: 296–299CrossRefPubMedGoogle Scholar
  72. 72.
    Midgley CA, Lane DP (1997) p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding. Oncogene 15: 1179–1189CrossRefPubMedGoogle Scholar
  73. 73.
    Buschmann T, Minamoto T, Wagle N, Fuchs SY, Adler V, Mai M, Ronai Z (2000) Analysis of JNK, Mdm2 and p14(ARF) contribution to the regulation of mutant p53 stability. J Mol Biol 295: 1009–10021CrossRefPubMedGoogle Scholar
  74. 74.
    Sionov RV, Haupt Y (1999) The cellular response to p53: the decision between life and death. Oncogene 18: 6145–6157CrossRefPubMedGoogle Scholar
  75. 75.
    Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR, Kley N (1995) Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377: 646–649CrossRefPubMedGoogle Scholar
  76. 76.
    Friesen C, Herr I, Krammer PH, Debatin KM (1996) Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat Med 2: 574–577CrossRefPubMedGoogle Scholar
  77. 77.
    Soengas MS, Alarcon RM, Yoshida H, Giaccia AJ, Hakem R, Mak TW, Lowe SW (1999) Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science 284: 156–159CrossRefPubMedGoogle Scholar
  78. 78.
    Yin C, Knudson CM, Korsmeyer SJ, Van Dyke T (1997) Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 385: 637–640CrossRefPubMedGoogle Scholar
  79. 79.
    Erster S, Mihara M, Kim RH, Petrenko O, Moll UM (2004) In vivo mitochondrial p53 translocation triggers a rapid first wave of cell death in response to DNA damage that can precede p53 target gene activation. Mol Cell Biol 24: 6728–6741CrossRefPubMedGoogle Scholar
  80. 80.
    Leu JI, Dumont P, Hafey M, Murphy ME, George DL (2004) Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 6: 443–450CrossRefPubMedGoogle Scholar
  81. 81.
    Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, Perucho M (1997) Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275: 967–969CrossRefPubMedGoogle Scholar
  82. 82.
    Kondo S, Shinomura Y, Miyazaki Y, Kiyohara T, Tsutsui S, Kitamura S, Nagasawa Y, Nakahara M, Kanayama S, Matsuzawa Y (2000) Mutations of the bak gene in human gastric and colorectal cancers. Cancer Res 60: 4328–4330PubMedGoogle Scholar
  83. 83.
    Mrozek A, Petrowsky H, Sturm I, Kraus J, Hermann S, Hauptmann S, Lorenz M, Dorken B, Daniel PT (2003) Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability. Cell Death Differ 10: 461–467PubMedGoogle Scholar
  84. 84.
    Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108: 153–164CrossRefPubMedGoogle Scholar
  85. 85.
    Reed JC (1999) Dysregulation of apoptosis in cancer. J Clin Oncol 17: 2941–2953PubMedGoogle Scholar
  86. 86.
    Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13: 2905–2927CrossRefPubMedGoogle Scholar
  87. 87.
    Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91: 231–241CrossRefPubMedGoogle Scholar
  88. 88.
    del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278: 687–689CrossRefPubMedGoogle Scholar
  89. 89.
    Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Wan M, Dubeau L, Scambia G, Masciullo V et al. (1995) Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 64: 280–285PubMedGoogle Scholar
  90. 90.
    Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR (1996) Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 93: 3636–3641PubMedGoogle Scholar
  91. 91.
    Mayo LD, Dixon JE, Durden DL, Tonks NK, Donner DB (2002) PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem 277: 5484–5489PubMedGoogle Scholar
  92. 92.
    Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J, Lowe SW (2004) Survival signaling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428: 332–337CrossRefPubMedGoogle Scholar
  93. 93.
    Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C (2003) PI3K/Akt and apoptosis: size matters. Oncogene 22: 8983–8998CrossRefPubMedGoogle Scholar
  94. 94.
    el-Deiry WS (1997) Role of oncogenes in resistance and killing by cancer therapeutic agents. Curr Opin Oncol 9: 79–87PubMedGoogle Scholar
  95. 95.
    Roymans D, Slegers H (2001) Phosphatidylinositol 3-kinases in tumor progression. Eur J Biochem 268: 487–498CrossRefPubMedGoogle Scholar
  96. 96.
    Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100: 387–390PubMedGoogle Scholar
  97. 97.
    Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M (2004) PI3K/Akt signaling pathway and cancer. Cancer Treat Rev 30: 193–204PubMedGoogle Scholar
  98. 98.
    Simpson L, Parsons R (2001) PTEN: life as a tumor suppressor. Exp Cell Res 264: 29–41CrossRefPubMedGoogle Scholar
  99. 99.
    Rosen D, Li JH, Keidar S, Markon I, Orda R, Berke G (2000) Tumor immunity in perforin-deficient mice: a role for CD95 (Fas/APO-1). J Immunol 164: 3229–3235PubMedGoogle Scholar
  100. 100.
    Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, Iwakura Y, Yagita H, Okumura K (2001) Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 7: 94–100CrossRefPubMedGoogle Scholar
  101. 101.
    Muschen M, Warskulat U, Beckmann MW (2000) Defining CD95 as a tumor suppressor gene. J Mol Med 78: 312–325PubMedGoogle Scholar
  102. 102.
    Shin MS, Kim HS, Lee SH, Park WS, Kim SY, Park JY, Lee JH, Lee SK, Lee SN, Jung SS et al. (2001) 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 61: 4942–4946PubMedGoogle Scholar
  103. 103.
    Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ (2000) Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 6: 529–535PubMedGoogle Scholar
  104. 104.
    Tepper CG, Seldin MF (1999) Modulation of caspase-8 and FLICE-inhibitory protein expression as a potential mechanism of Epstein-Barr virus tumorigenesis in Burkitt’s lymphoma. Blood 94: 1727–1737PubMedGoogle Scholar
  105. 105.
    Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA et al. (2001) Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409: 207–211CrossRefPubMedGoogle Scholar
  106. 106.
    Dai DL, Martinka M, Bush JA, Li G (2004) Reduced Apaf-1 expression in human cutaneous melanomas. Br J Cancer 91: 1089–1095PubMedGoogle Scholar
  107. 107.
    Hersey P, Zhang XD (2003) Overcoming resistance of cancer cells to apoptosis. J Cell Physiol 196: 9–18CrossRefPubMedGoogle Scholar
  108. 108.
    Bilim V, Kasahara T, Hara N, Takahashi K, Tomita Y (2003) Role of XIAP in the malignant phenotype of transitional cell cancer (TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistant TCC in vitro. Int J Cancer 103: 29–37CrossRefPubMedGoogle Scholar
  109. 109.
    Fong WG, Liston P, Rajcan-Separovic E, St Jean M, Craig C, Korneluk RG (2000) Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. Genomics 70: 113–122CrossRefPubMedGoogle Scholar
  110. 110.
    Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P, Iyer V, Jeffrey SS, Van de Rijn M, Waltham M et al. (2000) Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet 24: 227–235PubMedGoogle Scholar
  111. 111.
    Tamm I, Kornblau SM, Segall H, Krajewski S, Welsh K, Kitada S, Scudiero DA, Tudor G, Qui YH, Monks A et al. (2000) Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res 6: 1796–1803PubMedGoogle Scholar
  112. 112.
    Yang L, Mashima T, Sato S, Mochizuki M, Sakamoto H, Yamori T, Oh-Hara T, Tsuruo T (2003) 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 63: 831–837PubMedGoogle Scholar
  113. 113.
    Parton M, Krajewski S, Smith I, Krajewska M, Archer C, Naito M, Ahern R, Reed J, Dowsett M (2002) Coordinate expression of apoptosis-associated proteins in human breast cancer before and during chemotherapy. Clin Cancer Res 8: 2100–2108PubMedGoogle Scholar
  114. 114.
    Yang L, Cao Z, Yan H, Wood WC (2003) Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. Cancer Res 63: 6815–6824PubMedGoogle Scholar
  115. 115.
    Sasaki H, Sheng Y, Kotsuji F, Tsang BK (2000) Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells. Cancer Res 60: 5659–5666PubMedGoogle Scholar
  116. 116.
    Schimmer AD, Welsh K, Pinilla C, Wang Z, Krajewska M, Bonneau MJ, Pedersen IM, Kitada S, Scott FL, Bailly-Maitre B et al. (2004) Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell 5: 25–35CrossRefPubMedGoogle Scholar
  117. 117.
    Okano H, Shiraki K, Inoue H, Kawakita T, Saitou Y, Enokimura N, Yamamoto N, Sugimoto K, Fujikawa K, Murata K et al. (2003) Over-expression of Smac promotes TRAIL-induced cell death in human hepatocellular carcinoma. Int J Mol Med 12: 25–28PubMedGoogle Scholar
  118. 118.
    Yoo NJ, Kim HS, Kim SY, Park WS, Park CH, Jeon HM, Jung ES, Lee JY, Lee SH (2003) Immunohistochemical analysis of Smac/DIABLO expression in human carcinomas and sarcomas. APMIS 111: 382–388PubMedGoogle Scholar
  119. 119.
    McNeish IA, Bell S, McKay T, Tenev T, Marani M, Lemoine NR (2003) Expression of Smac/DIABLO in ovarian carcinoma cells induces apoptosis via a caspase-9-mediated pathway. Exp Cell Res 286: 186–198CrossRefPubMedGoogle Scholar
  120. 120.
    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: 808–815PubMedGoogle Scholar
  121. 121.
    Yang QH, Church-Hajduk R, Ren J, Newton ML, Du C (2003) Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes Dev 17: 1487–1496CrossRefPubMedGoogle Scholar
  122. 122.
    Ravi R, Bedi A (2004) NF-kappaB in cancer — a friend turned foe. Drug Resist Update 7: 53–67Google Scholar
  123. 123.
    Shishodia S, Aggarwal BB (2004) Nuclear factor-kappaB: a friend or a foe in cancer? Biochem Pharmacol 68: 1071–1080CrossRefPubMedGoogle Scholar
  124. 124.
    Baldwin AS (2001) Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 107: 241–246PubMedGoogle Scholar
  125. 125.
    Lee R, Collins T (2001) Nuclear factor-kappaB and cell survival: IAPs call for support. Circ Res 88: 262–264PubMedGoogle Scholar
  126. 126.
    Bell JC, Lichty B, Stojdl D (2003) Getting oncolytic virus therapies off the ground. Cancer Cell 4: 7–11CrossRefPubMedGoogle Scholar
  127. 127.
    Denicourt C, Dowdy SF (2004) MEDICINE: Targeting Apoptotic Pathways in Cancer Cells. Science 305: 1411–1413CrossRefPubMedGoogle Scholar
  128. 128.
    Shankar S, Srivastava RK (2004) Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications. Drug Resist Update 7: 139–156Google Scholar
  129. 129.
    Wetzker R, Rommel C (2004) Phosphoinositide 3-kinases as targets for therapeutic intervention. Curr Pharm Des 10: 1915–1922CrossRefPubMedGoogle Scholar
  130. 130.
    Xiong HQ (2004) Molecular targeting therapy for pancreatic cancer. Cancer Chemother Pharmacol 54: S69–S77PubMedGoogle Scholar
  131. 131.
    Jansen B, Schlagbauer-Wadl H, Brown BD, Bryan RN, van Elsas A, Muller M, Wolff K, Eichler HG, Pehamberger H (1998) bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat Med 4: 232–234CrossRefPubMedGoogle Scholar
  132. 132.
    Wacheck V, Heere-Ress E, Halaschek-Wiener J, Lucas T, Meyer H, Eichler HG, Jansen B (2001) Bcl-2 antisense oligonucleotides chemosensitize human gastric cancer in a SCID mouse xeno-transplantation model. J Mol Med 79: 587–593CrossRefPubMedGoogle Scholar
  133. 133.
    Chi KN, Gleave ME, Klasa R, Murray N, Bryce C, Lopes de Menezes DE, D’Aloisio S, Tolcher AW (2001) A phase I dose-finding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer. Clin Cancer Res 7: 3920–3927PubMedGoogle Scholar
  134. 134.
    Han Z, Chatterjee D, Early J, Pantazis P, Hendrickson EA, Wyche JH (1996) Isolation and characterization of an apoptosis-resistant variant of human leukemia HL-60 cells that has switched expression from Bcl-2 to Bcl-xL. Cancer Res 56: 1621–1628PubMedGoogle Scholar
  135. 135.
    Gautschi O, Tschopp S, Olie RA, Leech SH, Simoes-Wust AP, Ziegler A, Baumann B, Odermatt B, Hall J, Stahel RA et al. (2001) Activity of a novel bcl-2/bcl-xL-bispecific antisense oligonucleotide against tumors of diverse histologic origins. J Natl Cancer Inst 93: 463–471CrossRefPubMedGoogle Scholar
  136. 136.
    Wang S, Yang D, Lippman ME (2003) Targeting Bcl-2 and Bcl-XL with nonpeptidic small-molecule antagonists. Semin Oncol 30: 133–142CrossRefPubMedGoogle Scholar
  137. 137.
    Shinoura N, Hamada H (2003) Gene therapy using an adenovirus vector for apoptosis-related genes is a highly effective therapeutic modality for killing glioma cells. Curr Gene Ther 3: 147–153CrossRefPubMedGoogle Scholar
  138. 138.
    Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ (2002) Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2: 183–192CrossRefPubMedGoogle Scholar
  139. 139.
    Holcik M, Korneluk RG (2001) XIAP, the guardian angel. Nat Rev Mol Cell Biol 2: 550–556CrossRefPubMedGoogle Scholar
  140. 140.
    Hu Y, Cherton-Horvat G, Dragowska V, Baird S, Korneluk RG, Durkin JP, Mayer LD, LaCasse EC (2003) Antisense Oligonucleotides Targeting XIAP Induce Apoptosis and Enhance Chemotherapeutic Activity against Human Lung Cancer Cells in Vitro and in Vivo. Clin Cancer Res 9: 2826–2836PubMedGoogle Scholar
  141. 141.
    Holcik M, LaCasse EC, MacKenzie AE, Korneluk RG (eds): (2005) Apoptosis in Health and Disease: Clinical and Therapeutic Aspects. Cambridge University Press, Cambridge; in pressGoogle Scholar
  142. 142.
    Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG (2004) A Small Molecule Smac Mimic Potentiates TRAIL-and TNF{alpha}-Mediated Cell Death. Science 305: 1471–1474PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2006

Authors and Affiliations

  • Herman H. Cheung
    • 1
  • Vinay Arora
    • 1
  • Robert G. Korneluk
    • 1
  1. 1.Apoptosis Research CentreChildren’s Hospital of Eastern Ontario, Research InstituteOttawaCanada

Personalised recommendations