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How Cancer Cells Escape Death

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Cellular Respiration and Carcinogenesis

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Abstract

Programmed cell death, or apoptosis, is a cell-autonomous mechanism to restrict deviation from normal cellular function. Central to this mechanism are Bcl-2 proteins, which monitor normal cellular function to define apoptotic fate by surveying, integrating, and decoding multiple survival and proapoptotic signals from the intra and extra cellular environment. Escape from these restrictive mechanisms is essential to accommodate the cellular changes driving tumor establishment and development. To do so, many of the factors promoting tumorigenesis, such as genetic lesions, hypoxia, p53 mutations and oncogene activation, gain control over the main apoptotic pathway to promote cell survival. For this reason, the apoptotic pathway is the focus of remarkable interest for targeted cancer therapy development. However, as apoptosis evasion is a tumor promoting factor itself, the results of first therapeutic targeting attempts reveal that these targets pose drawbacks similar to the exhibited by classic oncogenic targets, including the rapid development of resistance through high mutation rate, intra and inter tumor heterogeneity and narrow effective range.

In addition to tumor promoting pathways, apoptosis evasion is fostered by factors secondary to transformation and tumor development. These factors, such as changes in the interaction with the extracellular environment and metabolism, have received less attention because of their underestimated role in transformation but might prove to be fruitful avenues for intervention as they are common to many tissues and affect apoptotic fate under the influence of reduced oncogenic pressure. The significance of these factors with respect to apoptosis evasion and their potential impact for therapy development are discussed.

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References

  1. Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2002; 2:277–288.

    Article  PubMed  CAS  Google Scholar 

  2. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004; 116:205–219.

    Article  PubMed  CAS  Google Scholar 

  3. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007; 26:1324–1337.

    Article  PubMed  CAS  Google Scholar 

  4. 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.

    Article  PubMed  CAS  Google Scholar 

  5. 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.

    Article  PubMed  CAS  Google Scholar 

  6. Brenner C, Grimm S. The permeability transition pore complex in cancer cell death. Oncogene 2006; 25:4744–4756.

    Article  PubMed  CAS  Google Scholar 

  7. Bouchier-Hayes L, Lartigue L, Newmeyer DD. Mitochondria: pharmacological manipulation of cell death. J Clin Invest 2005; 115:2640–2647.

    Article  PubMed  CAS  Google Scholar 

  8. Chipuk JE, Green DR. Do inducers of apoptosis trigger caspase-independent cell death? Nat Rev Mol Cell Biol 2005; 6:268–275.

    Article  PubMed  CAS  Google Scholar 

  9. Schafer ZT, Kornbluth S. The apoptosome: physiological, developmental, and pathological modes of regulation. Dev Cell 2006; 10:549–561.

    Article  PubMed  CAS  Google Scholar 

  10. Vahsen N, Cande C, Briere JJ, et al. AIF deficiency compromises oxidative phosphorylation. EMBO J 2004; 23:4679–4689.

    Article  PubMed  CAS  Google Scholar 

  11. Boatright KM, Salvesen GS. Mechanisms of caspase activation. Curr Opin Cell Biol 2003; 15:725–731.

    Article  PubMed  CAS  Google Scholar 

  12. Riedl SJ, Shi Y. Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 2004; 5:897–907.

    Article  PubMed  CAS  Google Scholar 

  13. Scott CL, Schuler M, Marsden VS, et al. Apaf-1 and caspase-9 do not act as tumor suppressors in myc-induced lymphomagenesis or mouse embryo fibroblast transformation. J Cell Biol 2004; 164:89–96.

    Article  PubMed  CAS  Google Scholar 

  14. Berezovskaya O, Schimmer AD, Glinskii AB, et al. Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. Cancer Res 2005; 65:2378–2386.

    Article  PubMed  CAS  Google Scholar 

  15. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997; 3:917–921.

    Article  PubMed  CAS  Google Scholar 

  16. Debnath J, Mills KR, Collins NL, Reginato MJ, Muthuswamy SK, Brugge JS. The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini. Cell 2002; 111:29–40.

    Article  PubMed  CAS  Google Scholar 

  17. Allen SM, Florell SR, Hanks AN, et al. Survivin expression in mouse skin prevents papilloma regression and promotes chemical-induced tumor progression. Cancer Res 2003; 63:567–572.

    PubMed  CAS  Google Scholar 

  18. Navarro P, Gomez M, Pizarro A, Gamallo C, Quintanilla M, Cano A. A role for the E-cadherin cell-cell adhesion molecule during tumor progression of mouse epidermal carcinogenesis. J Cell Biol 1991; 115:517–533.

    Article  PubMed  CAS  Google Scholar 

  19. Derksen PW, Liu X, Saridin F, et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 2006; 10:437–449.

    Article  PubMed  CAS  Google Scholar 

  20. Boudreau N, Sympson CJ, Werb Z, Bissell MJ. Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 1995; 267:891–893.

    Article  PubMed  CAS  Google Scholar 

  21. Kheradmand F, Werner E, Tremble P, Symons M, Werb Z. Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science 1998; 280:898–902.

    Article  PubMed  CAS  Google Scholar 

  22. Marconi A, Atzei P, Panza C, et al. FLICE/caspase-8 activation triggers anoikis induced by beta1-integrin blockade in human keratinocytes. J Cell Sci 2004; 117:5815–5823.

    Article  PubMed  CAS  Google Scholar 

  23. Gilmore AP, Metcalfe AD, Romer LH, Streuli CH. Integrin-mediated survival signals regulate the apoptotic function of Bax through its conformation and subcellular localization. J Cell Biol 2000; 149:431–446.

    Article  PubMed  CAS  Google Scholar 

  24. Puthalakath H, Villunger A, O'Reilly LA, et al. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 2001; 293:1829–1832.

    Article  PubMed  CAS  Google Scholar 

  25. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells. Surgery 2004; 135:555–562.

    Article  PubMed  CAS  Google Scholar 

  26. Mazelin L, Bernet A, Bonod-Bidaud C, et al. Netrin-1 controls colorectal tumorigenesis by regulating apoptosis. Nature 2004; 431:80–184.

    Article  PubMed  CAS  Google Scholar 

  27. Janes SM, Watt FM. Switch from alphavbeta5 to alphavbeta6 integrin expression protects squamous cell carcinomas from anoikis. J Cell Biol 2004; 166:419–431.

    Article  PubMed  CAS  Google Scholar 

  28. Munk Pedersen I, Reed J. Microenvironmental interactions and survival of CLL B-cells. Leuk Lymphoma 2004; 45:2365–2372.

    Article  PubMed  CAS  Google Scholar 

  29. Nefedova Y, Landowski TH, Dalton WS. Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms. Leukemia 2003; 17:1175–1182.

    Article  PubMed  CAS  Google Scholar 

  30. Sharma SV, Gajowniczek P, Way IP, et al. A common signaling cascade may underlie ``addiction" to the Src, BCR-ABL, and EGF receptor oncogenes. Cancer Cell 2006; 10:425–435.

    Article  PubMed  CAS  Google Scholar 

  31. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004; 10:789–799.

    Article  PubMed  CAS  Google Scholar 

  32. Breitschopf K, Haendeler J, Malchow P, Zeiher AM, Dimmeler S. Posttranslational modification of Bcl-2 facilitates its proteasome-dependent degradation: molecular characterization of the involved signaling pathway. Mol Cell Biol 2000; 20:1886–1896.

    Article  PubMed  CAS  Google Scholar 

  33. McCormick F. Cancer: survival pathways meet their end. Nature 2004; 428:267–269.

    Article  PubMed  CAS  Google Scholar 

  34. Zhou XM, Liu Y, Payne G, Lutz RJ, Chittenden T. Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser155. J Biol Chem 2000; 275: 25046–25051.

    Article  PubMed  CAS  Google Scholar 

  35. Hammerman PS, Fox CJ, Thompson CB. Beginnings of a signal-transduction pathway for bioenergetic control of cell survival. Trends Biochem Sci 2004; 29:586–592.

    Article  PubMed  CAS  Google Scholar 

  36. Bartkova J, Horejsi Z, Koed K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 2005; 434:864–870.

    Article  PubMed  CAS  Google Scholar 

  37. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell 1997; 88:323–331.

    Article  PubMed  CAS  Google Scholar 

  38. Schmitt CA, Fridman JS, Yang M, Baranov E, Hoffman RM, Lowe SW. Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 2002; 1:289–298.

    Article  PubMed  CAS  Google Scholar 

  39. Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007; 445:656–660.

    Article  PubMed  CAS  Google Scholar 

  40. Green DR, Chipuk JE. p53 and metabolism: inside the TIGAR. Cell 2006; 126:30–32.

    Article  PubMed  CAS  Google Scholar 

  41. Pelicano H, Martin DS, Xu RH, Huang P. Glycolysis inhibition for anticancer treatment. Oncogene 2006; 25:4633–4646.

    Article  PubMed  CAS  Google Scholar 

  42. Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB. Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol 2001; 21:5899–5912.

    Article  PubMed  CAS  Google Scholar 

  43. Shim H, Chun YS, Lewis BC, Dang CV. A unique glucose-dependent apoptotic pathway induced by c-Myc. Proc Natl Acad Sci USA 1998; 95:1511–1516.

    Article  PubMed  CAS  Google Scholar 

  44. Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 2001; 15:1406–1418.

    Article  PubMed  CAS  Google Scholar 

  45. Xu RH, Pelicano H, Zhou Y, et al. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 2005; 65:613–621.

    Article  PubMed  CAS  Google Scholar 

  46. Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006; 441:437–443.

    Article  PubMed  CAS  Google Scholar 

  47. Kim JY, Ahn HJ, Ryu JH, Suk K, Park JH. BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha. J Exp Med 2004; 199:113–124.

    Article  PubMed  CAS  Google Scholar 

  48. Vande Velde C, Cizeau J, Dubik D, et al. BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol 2000; 20:5454–5468.

    Article  PubMed  CAS  Google Scholar 

  49. Koshikawa N, Maejima C, Miyazaki K, Nakagawara A, Takenaga K. Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors. Oncogene 2006; 25:917–928.

    Article  PubMed  CAS  Google Scholar 

  50. Reichert M, Steinbach JP, Supra P, Weller M. Modulation of growth and radiochemosensitivity of human malignant glioma cells by acidosis. Cancer 2002; 95:1113–1119.

    Article  PubMed  CAS  Google Scholar 

  51. Kubasiak LA, Hernandez OM, Bishopric NH, Webster KA. Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. Proc Natl Acad Sci USA 2002; 99:12825–12830.

    Article  PubMed  CAS  Google Scholar 

  52. Abbey CK, Borowsky AD, McGoldrick ET, et al. In vivo positron-emission tomography imaging of progression and transformation in a mouse model of mammary neoplasia. Proc Natl Acad Sci USA 2004; 101:11438–11443.

    Article  PubMed  CAS  Google Scholar 

  53. Carew JS, Huang P. Mitochondrial defects in cancer. Mol. Cancer 2002; 1:9–21.

    Google Scholar 

  54. Jacobson MD, Burne JF, King MP, Miyashita T, Reed JC, Raff MC. Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA. Nature 1993; 361:365–369.

    Article  PubMed  CAS  Google Scholar 

  55. Vander Heiden MG, Chandel NS, Li XX, Schumacker PT, Colombini M, Thompson CB. Outer mitochondrial membrane permeability can regulate coupled respiration and cell survival. Proc Natl Acad Sci USA 2000; 97:4666–4671.

    Article  PubMed  CAS  Google Scholar 

  56. Fantin VR, Berardi MJ, Scorrano L, Korsmeyer SJ, Leder P. A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth. Cancer Cell 2002; 2:29–42.

    Article  PubMed  CAS  Google Scholar 

  57. Reed JC. Drug insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat Clin Pract Oncol 2006; 3:388–398.

    Article  PubMed  CAS  Google Scholar 

  58. Zeitlin BD, Joo E, Dong Z, et al. Antiangiogenic effect of TW37, a small-molecule inhibitor of Bcl-2. Cancer Res 2006; 66:8698–8706.

    Article  PubMed  CAS  Google Scholar 

  59. Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10:375–388.

    Article  PubMed  CAS  Google Scholar 

  60. Chauhan D, Neri P, Velankar M, et al. Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM). Blood 2007; 109:1220–1227.

    Article  PubMed  CAS  Google Scholar 

  61. Corso A, Ferretti E, Lunghi M, et al. Zoledronic acid down-regulates adhesion molecules of bone marrow stromal cells in multiple myeloma: a possible mechanism for its antitumor effect. Cancer 2005; 104:118–125.

    Article  PubMed  CAS  Google Scholar 

  62. Efstathiou E, Troncoso P, Wen S, et al. Initial modulation of the tumor microenvironment accounts for thalidomide activity in prostate cancer. Clin Cancer Res 2007; 13:1224–1231.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by an award from the American Heart Association and by grant number K22CA127136 from the National Cancer Institute.

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  1. Department of Cell Biology, School of Medicine, Emory University, Atlanta, GA, 30322

    Erica Werner

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    Werner, E. (2009). How Cancer Cells Escape Death. In: Sarangarajan, R., Apte, S. (eds) Cellular Respiration and Carcinogenesis. Humana Press. https://doi.org/10.1007/978-1-59745-435-3_12

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