Skip to main content
SpringerLink
Log in
Book cover

The Molecular Basis of Human Cancer pp 183–196Cite as

Senescence, Apoptosis, and Cancer

  • Chapter
  • First Online:

Abstract

Cancer cured in mice! Sounds hilarious to a nonacademic naive public, but for cancer researchers, every bit of information about cancer from worms, flies, and mice to human is immensely valuable. For a cancer biologist, it is not important to know in which living species on earth the cancer was cured, but how it was cured. We have learned a lot about the intricacy of signaling molecules and the underlying mechanisms involved in oncogenesis and cancer treatment. In this chapter, we review two important cellular properties, which are lost during cancer progression. These two properties, namely senescence and apoptosis, act as strong natural barriers to cancer. Vast majority of literature suggest that chemotherapeutics stop cancer progression by inducing apoptosis or cell death. In addition, the current literature also suggests that restoration of senescence in cancer cells by chemotherapeutic agents results in inhibition of cancer progression and in some cases even tumor regression.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.

    Article  CAS  PubMed  Google Scholar 

  2. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005;120:513–22.

    Article  CAS  PubMed  Google Scholar 

  3. Linskens MH, Harley CB, West MD, Campisi J, Hayflick L. Replicative senescence and cell death. Science. 1995;267:17.

    Article  CAS  PubMed  Google Scholar 

  4. Marcotte R, Lacelle C, Wang E. Senescent fibroblasts resist apoptosis by downregulating caspase-3. Mech Ageing Dev. 2004;125:777–83.

    Article  CAS  PubMed  Google Scholar 

  5. Dimri GP, Campisi J. Molecular and cell biology of replicative senescence. Cold Spring Harb Symp Quant Biol. 1994;59:67–73.

    Article  CAS  PubMed  Google Scholar 

  6. Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995;92:9363–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci. 2000;113:3613–22.

    CAS  PubMed  Google Scholar 

  8. Lee BY, Han JA, Im JS, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 2006;5:187–95.

    Article  CAS  PubMed  Google Scholar 

  9. Shelton DN, Chang E, Whittier PS, Choi D, Funk WD. Microarray analysis of replicative senescence. Curr Biol. 1999;9:939–45.

    Article  CAS  PubMed  Google Scholar 

  10. Dimri GP. What has senescence got to do with cancer? Cancer Cell. 2005;7:505–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sherr CJ, DePinho RA. Cellular senescence: mitotic clock or culture shock? Cell. 2000;102:407–10.

    Article  CAS  PubMed  Google Scholar 

  12. Itahana K, Campisi J, Dimri GP. Mechanisms of cellular senescence in human and mouse cells. Biogerontology. 2004;5:1–10.

    Article  CAS  PubMed  Google Scholar 

  13. Itahana K, Zou Y, Itahana Y, et al. Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol Cell Biol. 2003;23:389–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Stewart SA, Weinberg RA. Telomeres: cancer to human aging. Annu Rev Cell Dev Biol. 2006;22:531–57.

    Article  CAS  PubMed  Google Scholar 

  15. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–60.

    Article  CAS  PubMed  Google Scholar 

  16. Masutomi K, Yu EY, Khurts S, et al. Telomerase maintains telomere structure in normal human cells. Cell. 2003;114:241–53.

    Article  CAS  PubMed  Google Scholar 

  17. Bodnar AG, Ouellette M, Frolkis M, et al. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998;279:349–52.

    Article  CAS  PubMed  Google Scholar 

  18. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426:194–8.

    Article  PubMed  CAS  Google Scholar 

  19. Gire V, Roux P, Wynford-Thomas D, Brondello JM, Dulic V. DNA damage checkpoint kinase Chk2 triggers replicative senescence. EMBO J. 2004;23:2554–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003;13:1549–56.

    Article  CAS  PubMed  Google Scholar 

  21. Bartkova J, Rezaei N, Liontos M, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444:633–7.

    Article  CAS  PubMed  Google Scholar 

  22. Di Micco R, Fumagalli M, Cicalese A, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006;444:638–42.

    Article  PubMed  CAS  Google Scholar 

  23. Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell. 2004;14:501–13.

    Article  CAS  PubMed  Google Scholar 

  24. Brooks CL, Gu W. p53 ubiquitination: Mdm2 and beyond. Mol Cell. 2006;21:307–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eur J Cancer. 1997;33:787–91.

    Article  CAS  PubMed  Google Scholar 

  26. Shay JW, Wright WE. Telomerase therapeutics for cancer: challenges and new directions. Nat Rev Drug Discov. 2006;5:577–84.

    Article  CAS  PubMed  Google Scholar 

  27. Elenbaas B, Spirio L, Koerner F, et al. Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev. 2001;15:50–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hahn WC, Counter CM, Lundberg AS, et al. Creation of human tumour cells with defined genetic elements. Nature. 1999;400:464–8.

    Article  CAS  PubMed  Google Scholar 

  29. Dimri G, Band H, Band V. Mammary epithelial cell transformation: insights from cell culture and mouse models. Breast Cancer Res. 2005;7:171–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Feldser DM, Greider CW. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell. 2007;11:461–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cosme-Blanco W, Shen MF, Lazar AJ, et al. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence. EMBO Rep. 2007;8:497–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Damm K, Hemmann U, Garin-Chesa P, et al. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J. 2001;20:6958–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Seimiya H, Oh-hara T, Suzuki T, et al. Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-1991. Mol Cancer Ther. 2002;1:657–65.

    CAS  PubMed  Google Scholar 

  34. Riou JF, Guittat L, Mailliet P, et al. Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands. Proc Natl Acad Sci U S A. 2002;99:2672–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kelland LR. Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics—current status and future prospects. Eur J Cancer. 2005;41:971–9.

    Article  CAS  PubMed  Google Scholar 

  36. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88:593–602.

    Article  CAS  PubMed  Google Scholar 

  37. Collado M, Serrano M. The power and the promise of oncogene-induced senescence markers. Nat Rev. 2006;6:472–6.

    Article  CAS  Google Scholar 

  38. Braig M, Lee S, Loddenkemper C, et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature. 2005;436:660–5.

    Article  CAS  PubMed  Google Scholar 

  39. Chen Z, Trotman LC, Shaffer D, et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436:725–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Collado M, Gil J, Efeyan A, et al. Tumour biology: senescence in premalignant tumours. Nature. 2005;436:642.

    Article  CAS  PubMed  Google Scholar 

  41. Michaloglou C, Vredeveld LC, Soengas MS, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436:720–4.

    Article  CAS  PubMed  Google Scholar 

  42. Campisi J. Suppressing cancer: the importance of being senescent. Science. 2005;309:886–7.

    Article  CAS  PubMed  Google Scholar 

  43. Shay JW, Roninson IB. Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene. 2004;23:2919–33.

    Article  CAS  PubMed  Google Scholar 

  44. Chang BD, Broude EV, Dokmanovic M, et al. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res. 1999;59:3761–7.

    CAS  PubMed  Google Scholar 

  45. Jackson JG, Pereira-Smith OM. Primary and compensatory roles for RB family members at cell cycle gene promoters that are deacetylated and downregulated in doxorubicin-induced senescence of breast cancer cells. Mol Cell Biol. 2006;26:2501–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zheng X, Chou PM, Mirkin BL, Rebbaa A. Senescence-initiated reversal of drug resistance: specific role of cathepsin L. Cancer Res. 2004;64:1773–80.

    Article  CAS  PubMed  Google Scholar 

  47. Rebbaa A, Zheng X, Chu F, Mirkin BL. The role of histone acetylation versus DNA damage in drug-induced senescence and apoptosis. Cell Death Differ. 2006;13:1960–7.

    Article  CAS  PubMed  Google Scholar 

  48. Wang Y, Blandino G, Oren M, Givol D. Induced p53 expression in lung cancer cell line promotes cell senescence and differentially modifies the cytotoxicity of anti-cancer drugs. Oncogene. 1998;17:1923–30.

    Article  CAS  PubMed  Google Scholar 

  49. Zhao W, Lin ZX, Zhang ZQ. Cisplatin-induced premature senescence with concomitant reduction of gap junctions in human fibroblasts. Cell Res. 2004;14:60–6.

    Article  CAS  PubMed  Google Scholar 

  50. Marusyk A, Wheeler LJ, Mathews CK, Degregori J. p53 mediates senescence-like arrest induced by chronic replicational stress. Mol Cell Biol. 2007;27:5336–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Narath R, Ambros IM, Kowalska A, et al. Induction of senescence in MYCN amplified neuroblastoma cell lines by hydroxyurea. Genes Chromosomes Cancer. 2007;46:130–42.

    Article  CAS  PubMed  Google Scholar 

  52. Park JI, Jeong JS, Han JY, et al. Hydroxyurea induces a senescence-like change of K562 human erythroleukemia cell. J Cancer Res Clin Oncol. 2000;126:455–60.

    Article  CAS  PubMed  Google Scholar 

  53. Cheng HL, Chang SM, Cheng YW, Liu HJ, Chen YC. Characterization of the activities of p21Cip1/Waf1 promoter-driven reporter systems during camptothecin-induced senescence-like state of BHK-21 cells. Mol Cell Biochem. 2006;291:29–38.

    Article  CAS  PubMed  Google Scholar 

  54. Han Z, Wei W, Dunaway S, et al. Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin. J Biol Chem. 2002;277:17154–60.

    Article  CAS  PubMed  Google Scholar 

  55. te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 2002;62:1876–83.

    Google Scholar 

  56. Roninson IB. Tumor cell senescence in cancer treatment. Cancer Res. 2003;63:2705–15.

    CAS  PubMed  Google Scholar 

  57. Roberson RS, Kussick SJ, Vallieres E, Chen SY, Wu DY. Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res. 2005;65:2795–803.

    Article  CAS  PubMed  Google Scholar 

  58. Schmitt CA, Fridman JS, Yang M, et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell. 2002;109:335–46.

    Article  CAS  PubMed  Google Scholar 

  59. Christov KT, Shilkaitis AL, Kim ES, Steele VE, Lubet RA. Chemopreventive agents induce a senescence-like phenotype in rat mammary tumours. Eur J Cancer. 2003;39:230–9.

    Article  CAS  PubMed  Google Scholar 

  60. Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007;28:622–9.

    Article  CAS  PubMed  Google Scholar 

  61. Soussi T. p53 alterations in human cancer: more questions than answers. Oncogene. 2007;26:2145–56.

    Article  CAS  PubMed  Google Scholar 

  62. Ventura A, Kirsch DG, McLaughlin ME, et al. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007;445:661–5.

    Article  CAS  PubMed  Google Scholar 

  63. Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007;445:656–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Green DR, Evan GI. A matter of life and death. Cancer Cell. 2002;1:19–30.

    Article  CAS  PubMed  Google Scholar 

  65. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  CAS  PubMed  Google Scholar 

  66. Lowe SW, Cepero E, Evan G. Intrinsic tumour suppression. Nature. 2004;432:307–15.

    Article  CAS  PubMed  Google Scholar 

  67. Meng XW, Lee SH, Kaufmann SH. Apoptosis in the treatment of cancer: a promise kept? Curr Opin Cell Biol. 2006;18:668–76.

    Article  CAS  PubMed  Google Scholar 

  68. Kerr JF. History of the events leading to the formulation of the apoptosis concept. Toxicology. 2002;181–182:471–4.

    Article  PubMed  Google Scholar 

  69. Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev. 2004;4:592–603.

    Article  CAS  Google Scholar 

  70. Bellamy CO, Malcomson RD, Harrison DJ, Wyllie AH. Cell death in health and disease: the biology and regulation of apoptosis. Semin Cancer Biol. 1995;6:3–16.

    Article  CAS  PubMed  Google Scholar 

  71. Wyllie AH, Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306.

    Article  CAS  PubMed  Google Scholar 

  72. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267:1456–62.

    Article  CAS  PubMed  Google Scholar 

  73. Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev. 2002;2:420–30.

    Article  CAS  Google Scholar 

  74. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205–19.

    Article  CAS  PubMed  Google Scholar 

  75. Adams JM, Huang DC, Strasser A, et al. Subversion of the Bcl-2 life/death switch in cancer development and therapy. Cold Spring Harb Symp Quant Biol. 2005;70:469–77.

    Article  CAS  PubMed  Google Scholar 

  76. Coultas L, Strasser A. The role of the Bcl-2 protein family in cancer. Semin Cancer Biol. 2003;13:115–23.

    Article  CAS  PubMed  Google Scholar 

  77. Oda E, Ohki R, Murasawa H, et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 2000;288:1053–8.

    Article  CAS  PubMed  Google Scholar 

  78. Vousden KH. Apoptosis. p53 and PUMA: a deadly duo. Science. 2005;309:1685–6.

    Article  CAS  PubMed  Google Scholar 

  79. Yu J, Zhang L. The transcriptional targets of p53 in apoptosis control. Biochem Biophys Res Commun. 2005;331:851–8.

    Article  CAS  PubMed  Google Scholar 

  80. Chipuk JE, Bouchier-Hayes L, Kuwana T, Newmeyer DD, Green DR. PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science. 2005;309:1732–5.

    Article  CAS  PubMed  Google Scholar 

  81. Chipuk JE, Kuwana T, Bouchier-Hayes L, et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 2004;303:1010–4.

    Article  CAS  PubMed  Google Scholar 

  82. Yan N, Shi Y. Mechanisms of apoptosis through structural biology. Annu Rev Cell Dev Biol. 2005;21:35–56.

    Article  CAS  PubMed  Google Scholar 

  83. 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;410:112–6.

    Article  CAS  PubMed  Google Scholar 

  84. 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  CAS  PubMed  Google Scholar 

  85. Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem. 1999;68:383–424.

    Article  CAS  PubMed  Google Scholar 

  86. Hail Jr N, Carter BZ, Konopleva M, Andreeff M. Apoptosis effector mechanisms: a requiem performed in different keys. Apoptosis. 2006;11:889–904.

    Article  PubMed  Google Scholar 

  87. Salvesen GS. Caspases and apoptosis. Essays Biochem. 2002;38:9–19.

    Article  CAS  PubMed  Google Scholar 

  88. Moffitt KL, Martin SL, Walker B. The emerging role of serine proteases in apoptosis. Biochem Soc Trans. 2007;35:559–60.

    Article  CAS  PubMed  Google Scholar 

  89. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002;108:153–64.

    Article  CAS  PubMed  Google Scholar 

  90. Owen-Schaub LB, Zhang W, Cusack JC, et al. Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol. 1995;15:3032–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 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;58:1593–8.

    CAS  PubMed  Google Scholar 

  92. Rahman-Roblick R, Roblick UJ, Hellman U, et al. p53 targets identified by protein expression profiling. Proc Natl Acad Sci U S A. 2007;104:5401–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kirkin V, Joos S, Zornig M. The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta. 2004;1644:229–49.

    Article  CAS  PubMed  Google Scholar 

  94. Reed JC. Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. Curr Opin Oncol. 1995;7:541–6.

    Article  CAS  PubMed  Google Scholar 

  95. Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell. 1986;47:19–28.

    Article  CAS  PubMed  Google Scholar 

  96. Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev. 2002;2:647–56.

    Article  CAS  Google Scholar 

  97. Wu J, Shao ZM, Shen ZZ, et al. Significance of apoptosis and apoptotic-related proteins, Bcl-2, and Bax in primary breast cancer. Breast J. 2000;6:44–52.

    Article  CAS  PubMed  Google Scholar 

  98. Kondo S, Shinomura Y, Miyazaki Y, et al. Mutations of the bak gene in human gastric and colorectal cancers. Cancer Res. 2000;60:4328–30.

    CAS  PubMed  Google Scholar 

  99. 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;91:479–89.

    Article  CAS  PubMed  Google Scholar 

  100. Baldi A, Santini D, Russo P, et al. Analysis of APAF-1 expression in human cutaneous melanoma progression. Exp Dermatol. 2004;13:93–7.

    Article  CAS  PubMed  Google Scholar 

  101. Zlobec I, Minoo P, Baker K, et al. Loss of APAF-1 expression is associated with tumour progression and adverse prognosis in colorectal cancer. Eur J Cancer. 2007;43:1101–7.

    Article  CAS  PubMed  Google Scholar 

  102. Christoph F, Kempkensteffen C, Weikert S, et al. Methylation of tumour suppressor genes APAF-1 and DAPK-1 and in vitro effects of demethylating agents in bladder and kidney cancer. Br J Cancer. 2006;95:1701–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Furukawa Y, Sutheesophon K, Wada T, et al. Methylation silencing of the Apaf-1 gene in acute leukemia. Mol Cancer Res. 2005;3:325–34.

    Article  CAS  PubMed  Google Scholar 

  104. Chim CS, Liang R, Fung TK, Choi CL, Kwong YL. Epigenetic dysregulation of the death-associated protein kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in multiple myeloma. J Clin Pathol. 2007;60:664–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Robles AI, Bemmels NA, Foraker AB, Harris CC. APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis. Cancer Res. 2001;61:6660–4.

    CAS  PubMed  Google Scholar 

  106. Cao C, Mu Y, Hallahan DE, Lu B. XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer. Oncogene. 2004;23:7047–52.

    Article  CAS  PubMed  Google Scholar 

  107. Lopes RB, Gangeswaran R, McNeish IA, Wang Y, Lemoine NR. Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy. Int J Cancer. 2007;120:2344–52.

    Article  CAS  PubMed  Google Scholar 

  108. Nemoto T, Kitagawa M, Hasegawa M, et al. Expression of IAP family proteins in esophageal cancer. Exp Mol Pathol. 2004;76:253–9.

    Article  CAS  PubMed  Google Scholar 

  109. Liu B, Han M, Wen JK, Wang L. Livin/ML-IAP as a new target for cancer treatment. Cancer Lett. 2007;250:168–76.

    Article  CAS  PubMed  Google Scholar 

  110. Shariat SF, Ashfaq R, Karakiewicz PI, et al. Survivin expression is associated with bladder cancer presence, stage, progression, and mortality. Cancer. 2007;109:1106–13.

    Article  CAS  PubMed  Google Scholar 

  111. Hinnis AR, Luckett JC, Walker RA. Survivin is an independent predictor of short-term survival in poor prognostic breast cancer patients. Br J Cancer. 2007;96:639–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ryan BM, Konecny GE, Kahlert S, et al. Survivin expression in breast cancer predicts clinical outcome and is associated with HER2, VEGF, urokinase plasminogen activator and PAI-1. Ann Oncol. 2006;17:597–604.

    Article  CAS  PubMed  Google Scholar 

  113. Lee MA, Park GS, Lee HJ, et al. Survivin expression and its clinical significance in pancreatic cancer. BMC Cancer. 2005;5:127.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Fangusaro JR, Caldas H, Jiang Y, Altura RA. Survivin: an inhibitor of apoptosis in pediatric cancer. Pediatr Blood Cancer. 2006;47:4–13.

    Article  PubMed  Google Scholar 

  115. Rosato A, Pivetta M, Parenti A, et al. Survivin in esophageal cancer: an accurate prognostic marker for squamous cell carcinoma but not adenocarcinoma. Int J Cancer. 2006;119:1717–22.

    Article  CAS  PubMed  Google Scholar 

  116. Tirro E, Consoli ML, Massimino M, et al. Altered expression of c-IAP1, survivin, and Smac contributes to chemotherapy resistance in thyroid cancer cells. Cancer Res. 2006;66:4263–72.

    Article  CAS  PubMed  Google Scholar 

  117. Nakano J, Huang CL, Liu D, et al. Survivin gene expression is negatively regulated by the p53 tumor suppressor gene in non-small cell lung cancer. Int J Oncol. 2005;27:1215–21.

    CAS  PubMed  Google Scholar 

  118. Ferrandina G, Legge F, Martinelli E, et al. Survivin expression in ovarian cancer and its correlation with clinico-pathological, surgical and apoptosis-related parameters. Br J Cancer. 2005;92:271–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Meng H, Lu C, Mabuchi H, Tanigawa N. Prognostic significance and different properties of survivin splicing variants in gastric cancer. Cancer Lett. 2004;216:147–55.

    Article  CAS  PubMed  Google Scholar 

  120. Fukuda S, Pelus LM. Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther. 2006;5:1087–98.

    Article  CAS  PubMed  Google Scholar 

  121. Park WS, Oh RR, Kim YS, et al. Somatic mutations in the death domain of the Fas (Apo-1/CD95) gene in gastric cancer. J Pathol. 2001;193:162–8.

    Article  CAS  PubMed  Google Scholar 

  122. Shin MS, Kim HS, Lee SH, et al. Alterations of Fas-pathway genes associated with nodal metastasis in non-small cell lung cancer. Oncogene. 2002;21:4129–36.

    Article  CAS  PubMed  Google Scholar 

  123. Bertoni F, Conconi A, Carobbio S, et al. Analysis of Fas/CD95 gene somatic mutations in ovarian cancer cell lines. Int J Cancer. 2000;86:450.

    Article  CAS  PubMed  Google Scholar 

  124. Butler LM, Hewett PJ, Butler WJ, Cowled PA. Down-regulation of Fas gene expression in colon cancer is not a result of allelic loss or gene rearrangement. Br J Cancer. 1998;77:1454–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Gratas C, Tohma Y, Barnas C, et al. Up-regulation of Fas (APO-1/CD95) ligand and down-regulation of Fas expression in human esophageal cancer. Cancer Res. 1998;58:2057–62.

    CAS  PubMed  Google Scholar 

  126. Muschen M, Rajewsky K, Kronke M, Kuppers R. The origin of CD95-gene mutations in B-cell lymphoma. Trends Immunol. 2002;23:75–80.

    Article  CAS  PubMed  Google Scholar 

  127. Muschen M, Warskulat U, Beckmann MW. Defining CD95 as a tumor suppressor gene. J Mol Med. 2000;78:312–25.

    Article  CAS  PubMed  Google Scholar 

  128. Shin MS, Kim HS, Lee SH, et al. Mutations of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers. Cancer Res. 2001;61:4942–6.

    CAS  PubMed  Google Scholar 

  129. Yang S, Liu J, Thor AD, Yang X. Caspase expression profile and functional activity in a panel of breast cancer cell lines. Oncol Rep. 2007;17:1229–35.

    CAS  PubMed  Google Scholar 

  130. Donehower LA. The p53-deficient mouse: a model for basic and applied cancer studies. Semin Cancer Biol. 1996;7:269–78.

    Article  CAS  PubMed  Google Scholar 

  131. Dudgeon C, Kek C, Demidov ON, et al. Tumor susceptibility and apoptosis defect in a mouse strain expressing a human p53 transgene. Cancer Res. 2006;66:2928–36.

    Article  CAS  PubMed  Google Scholar 

  132. Luo JL, Tong WM, Yoon JH, et al. UV-induced DNA damage and mutations in Hupki (human p53 knock-in) mice recapitulate p53 hotspot alterations in sun-exposed human skin. Cancer Res. 2001;61:8158–63.

    CAS  PubMed  Google Scholar 

  133. Luo JL, Yang Q, Tong WM, et al. Knock-in mice with a chimeric human/murine p53 gene develop normally and show wild-type p53 responses to DNA damaging agents: a new biomedical research tool. Oncogene. 2001;20:320–8.

    Article  CAS  PubMed  Google Scholar 

  134. Christophorou MA, Martin-Zanca D, Soucek L, et al. Temporal dissection of p53 function in vitro and in vivo. Nat Genet. 2005;37:718–26.

    Article  CAS  PubMed  Google Scholar 

  135. Martins CP, Brown-Swigart L, Evan GI. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell. 2006;127:1323–34.

    Article  CAS  PubMed  Google Scholar 

  136. Iwakuma T, Lozano G. Crippling p53 activities via knock-in mutations in mouse models. Oncogene. 2007;26:2177–84.

    Article  CAS  PubMed  Google Scholar 

  137. Liu G, Parant JM, Lang G, et al. Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet. 2004;36:63–8.

    Article  CAS  PubMed  Google Scholar 

  138. Chin L, Artandi SE, Shen Q, et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999;97:527–38.

    Article  CAS  PubMed  Google Scholar 

  139. Greenberg RA, Chin L, Femino A, et al. Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell. 1999;97:515–25.

    Article  CAS  PubMed  Google Scholar 

  140. Strasser A, O'Connor L, Huang DC, et al. Lessons from bcl-2 transgenic mice for immunology, cancer biology and cell death research. Behring Inst Mitt. 1996;(97):101–17.

    Google Scholar 

  141. McDonnell TJ, Deane N, Platt FM, et al. Bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 1989;57:79–88.

    Article  CAS  PubMed  Google Scholar 

  142. McDonnell TJ, Korsmeyer SJ. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature. 1991;349:254–6.

    Article  CAS  PubMed  Google Scholar 

  143. Bruckheimer EM, Brisbay S, Johnson DJ, et al. Bcl-2 accelerates multistep prostate carcinogenesis in vivo. Oncogene. 2000;19:5251–8.

    Article  CAS  PubMed  Google Scholar 

  144. Lee S, Chari NS, Kim HW, et al. Cooperation of Ha-ras and Bcl-2 during multistep skin carcinogenesis. Mol Carcinog. 2007;46:949–57.

    Article  CAS  PubMed  Google Scholar 

  145. Letai A, Sorcinelli MD, Beard C, Korsmeyer SJ. Antiapoptotic BCL-2 is required for maintenance of a model leukemia. Cancer Cell. 2004;6:241–9.

    Article  CAS  PubMed  Google Scholar 

  146. Jager R, Herzer U, Schenkel J, Weiher H. Overexpression of Bcl-2 inhibits alveolar cell apoptosis during involution and accelerates c-myc-induced tumorigenesis of the mammary gland in transgenic mice. Oncogene. 1997;15:1787–95.

    Article  CAS  PubMed  Google Scholar 

  147. Naik P, Karrim J, Hanahan D. The rise and fall of apoptosis during multistage tumorigenesis: down-modulation contributes to tumor progression from angiogenic progenitors. Genes Dev. 1996;10:2105–16.

    Article  CAS  PubMed  Google Scholar 

  148. Pena JC, Rudin CM, Thompson CB. A Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas. Cancer Res. 1998;58:2111–6.

    CAS  PubMed  Google Scholar 

  149. Carlo-Stella C, Lavazza C, Locatelli A, et al. Targeting TRAIL agonistic receptors for cancer therapy. Clin Cancer Res. 2007;13:2313–7.

    Article  CAS  PubMed  Google Scholar 

  150. Cretney E, Takeda K, Smyth MJ. Cancer: novel therapeutic strategies that exploit the TNF-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway. Int J Biochem Cell Biol. 2007;39:280–6.

    Article  CAS  PubMed  Google Scholar 

  151. Koschny R, Walczak H, Ganten TM. The promise of TRAIL-potential and risks of a novel anticancer therapy. J Mol Med. 2007;85:923–35.

    Article  CAS  PubMed  Google Scholar 

  152. Selivanova G, Wiman KG. Reactivation of mutant p53: molecular mechanisms and therapeutic potential. Oncogene. 2007;26:2243–54.

    Article  CAS  PubMed  Google Scholar 

  153. Barbieri E, Mehta P, Chen Z, et al. MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death. Mol Cancer Ther. 2006;5:2358–65.

    Article  CAS  PubMed  Google Scholar 

  154. Fotouhi N, Graves B. Small molecule inhibitors of p53/MDM2 interaction. Curr Top Med Chem. 2005;5:159–65.

    Article  CAS  PubMed  Google Scholar 

  155. Issaeva N, Bozko P, Enge M, et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med. 2004;10:1321–8.

    Article  CAS  PubMed  Google Scholar 

  156. Tovar C, Rosinski J, Filipovic Z, et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci U S A. 2006;103:1888–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Van Maerken T, Speleman F, Vermeulen J, et al. Small-molecule MDM2 antagonists as a new therapy concept for neuroblastoma. Cancer Res. 2006;66:9646–55.

    Article  PubMed  CAS  Google Scholar 

  158. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–8.

    Article  CAS  PubMed  Google Scholar 

  159. Bielas JH, Loeb KR, Rubin BP, True LD, Loeb LA. Human cancers express a mutator phenotype. Proc Natl Acad Sci U S A. 2006;103:18238–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Sjoblom T, Jones S, Wood LD, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314:268–74.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Grant support from National Cancer Institute (R01 CA094150) and the Department of Defense (DAMD17-02-1-0509) to GPD, and contribution of our past and present collaborators is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, George Washington University, 2300 Eye St., NW, Washington, DC, 20037, USA

    Manjari Dimri M.B.B.S. & Goberdhan P. Dimri Ph.D.

Authors
  1. Manjari Dimri M.B.B.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Goberdhan P. Dimri Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Goberdhan P. Dimri Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Curriculum in Toxicology, UNC Program in Translational Medicine, UNC Lineberger Comprehensive Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

    William B. Coleman

  2. Laboratory for Clinical Genomics and Advanced Technology (CGAT), Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, Hanover, New Hampshire, USA

    Gregory J. Tsongalis

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media New York

About this chapter

Cite this chapter

Dimri, M., Dimri, G.P. (2017). Senescence, Apoptosis, and Cancer. In: Coleman, W., Tsongalis, G. (eds) The Molecular Basis of Human Cancer. Humana Press, New York, NY. https://doi.org/10.1007/978-1-59745-458-2_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-458-2_10

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-934115-18-3

  • Online ISBN: 978-1-59745-458-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation