Abstract
Apoptosis is programmed cell death, which sustains the equilibrium between survival and death in eukaryotic cells. It is a tightly regulated cell death program that aims at eliminating harmful, damaged, or unwanted cells. This wisely programmed cell death is central in the development of all multicellular organisms, which is highlighted by the prevalence of diseases associated with abnormal apoptosis. For example, defect in apoptosis is a hallmark of cancer, whereas excessive cell death occurs in several neurodegenerative disorders. The cell death signals are responsible for maintenance of the genomic integrity, while defective cell death may stimulate carcinogenesis. These signals are convoluted and are controlled at various points. Tumor cells survive by taking help of several different molecular mechanisms to inhibit apoptosis and acquire resistance to apoptotic agents, for example, by the expression of anti-apoptotic proteins such as Bcl-2 or by the downregulation or mutation of pro-apoptotic proteins such as BAX. This chapter includes recent developments in the field and reviews new evidences of the interconnection between apoptosis and cancer. Various molecules that can be regulated to facilitate apoptosis in myriad of cancers are also enlisted. Overall, the chapter discusses about the development of various treatments and approaches to combat cancer by targeting anti-apoptotic proteins belonging to Bcl-2 and IAP families.
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References
Vaux DL, Korsmeyer SJ (1999) Cell death in development. Cell 96(2):245–254
Wong RS (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30:87
Letai AG (2008) Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer 8(2):121–132
Vo TT, Letai A (2010) BH3-only proteins and their effects on cancer. Adv Exp Med Biol 687:49–63
Yu L et al (2004) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304(5676):1500–1502
Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87(1):99–163
Bender T, Martinou JC (2013) Where killers meet--permeabilization of the outer mitochondrial membrane during apoptosis. Cold Spring Harb Perspect Biol 5(1):a011106
Bradley JR, Pober JS (2001) Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene 20(44):6482–6491
Hengartner MO (2001) Apoptosis: corralling the corpses. Cell 104(3):325–328
Singh N, Hassan A, Bose K (2016) Molecular basis of death effector domain chain assembly and its role in caspase-8 activation. FASEB J 30(1):186–200
Schneider P, Tschopp J (2000) Apoptosis induced by death receptors. Pharm Acta Helv 74(2–3):281–286
Koyama S, Koike N, Adachi S (2001) Fas receptor counterattack against tumor-infiltrating lymphocytes in vivo as a mechanism of immune escape in gastric carcinoma. J Cancer Res Clin Oncol 127(1):20–26
Hengartner MO (2000) The biochemistry of apoptosis. Nature 407(6805):770–776
Hakem R et al (1998) Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94(3):339–352
Kuida K et al (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94(3):325–337
Hector S et al (2012) Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy. Gut 61(5):725–733
Reed JC (2006) Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ 13(8):1378–1386
Green DR (2006) At the gates of death. Cancer Cell 9(5):328–330
Amundson SA et al (2000) An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res 60(21):6101–6110
Trapani JA, Smyth MJ (2002) Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2(10):735–747
King KL, Cidlowski JA (1998) Cell cycle regulation and apoptosis. Annu Rev Physiol 60:601–617
Kerr JF, Searle J (1972) A mode of cell loss in malignant neoplasms. J Pathol 106(1):xi
Miyashita T et al (1994) Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9(6):1799–1805
Vaux DL (1998) Immunopathology of apoptosis--introduction and overview. Springer Semin Immunopathol 19(3):271–278
Strasser A, Cory S, Adams JM (2011) Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases. EMBO J 30(18):3667–3683
Certo M et al (2006) Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9(5):351–365
Garcia-Saez AJ (2012) The secrets of the Bcl-2 family. Cell Death Differ 19(11):1733–1740
Wei MC et al (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292(5517):727–730
Raffo AJ et al (1995) Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res 55(19):4438–4445
Fulda S, Meyer E, Debatin KM (2002) Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. Oncogene 21(15):2283–2294
Goolsby C et al (2005) Bcl-2 regulatory pathway is functional in chronic lymphocytic leukemia. Cytometry B Clin Cytom 63(1):36–46
Deng J et al (2007) BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 12(2):171–185
Hanada M et al (1993) bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 82(6):1820–1828
Gala JL et al (1994) High expression of bcl-2 is the rule in acute lymphoblastic leukemia, except in Burkitt subtype at presentation, and is not correlated with the prognosis. Ann Hematol 69(1):17–24
Tsujimoto Y et al (1984) Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226(4678):1097–1099
Chen-Levy Z, Nourse J, Cleary ML (1989) The bcl-2 candidate proto-oncogene product is a 24-kilodalton integral-membrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14;18) translocation. Mol Cell Biol 9(2):701–710
Hermine O et al (1996) Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin's lymphoma. Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood 87(1):265–272
Karnak D, Xu L (2010) Chemosensitization of prostate cancer by modulating Bcl-2 family proteins. Curr Drug Targets 11(6):699–707
Hellemans P et al (1995) Prognostic value of bcl-2 expression in invasive breast cancer. Br J Cancer 72(2):354–360
Jiang SX et al (1995) Expression of bcl-2 oncogene protein is prevalent in small cell lung carcinomas. J Pathol 177(2):135–138
Anagnostou VK et al (2010) High expression of BCL-2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology. BMC Cancer 10:186
Henriksen R, Wilander E, Oberg K (1995) Expression and prognostic significance of Bcl-2 in ovarian tumours. Br J Cancer 72(5):1324–1329
Lamers F et al (2012) Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth. Eur J Cancer 48(16):3093–3103
Swellam M et al (2004) Incidence of Bcl-2 expression in bladder cancer: relation to schistosomiasis. Clin Biochem 37(9):798–802
Zhao DP et al (2005) Prognostic significance of bcl-2 and p53 expression in colorectal carcinoma. J Zhejiang Univ Sci B 6(12):1163–1169
Pena JC et al (1999) Bcl-xL and Bcl-2 expression in squamous cell carcinoma of the head and neck. Cancer 85(1):164–170
Campos L et al (1993) High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 81(11):3091–3096
Huang JZ et al (2002) The t(14;18) defines a unique subset of diffuse large B-cell lymphoma with a germinal center B-cell gene expression profile. Blood 99(7):2285–2290
Iqbal J et al (2006) BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. J Clin Oncol 24(6):961–968
Levine AJ, Momand J, Finlay CA (1991) The p53 tumour suppressor gene. Nature 351(6326):453–456
Oren M, Rotter V (1999) Introduction: p53 – the first twenty years. Cell Mol Life Sci 55(1):9–11
Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358(6381):15–16
Avery-Kiejda KA et al (2011) P53 in human melanoma fails to regulate target genes associated with apoptosis and the cell cycle and may contribute to proliferation. BMC Cancer 11:203
Slatter TL et al (2011) Hyperproliferation, cancer, and inflammation in mice expressing a Delta133p53-like isoform. Blood 117(19):5166–5177
Vikhanskaya F et al (2007) Cancer-derived p53 mutants suppress p53-target gene expression--potential mechanism for gain of function of mutant p53. Nucleic Acids Res 35(6):2093–2104
LaCasse EC et al (2008) IAP-targeted therapies for cancer. Oncogene 27(48):6252–6275
Vucic D, Fairbrother WJ (2007) The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clin Cancer Res 13(20):5995–6000
Wei Y, Fan T, Yu M (2008) Inhibitor of apoptosis proteins and apoptosis. Acta Biochim Biophys Sin Shanghai 40(4):278–288
Lopes RB et al (2007) Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy. Int J Cancer 120(11):2344–2352
Vucic D et al (2000) ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol 10(21):1359–1366
Ashhab Y et al (2001) Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern. FEBS Lett 495(1–2):56–60
Chen Z et al (1999) A human IAP-family gene, apollon, expressed in human brain cancer cells. Biochem Biophys Res Commun 264(3):847–854
Krepela E et al (2009) Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma. Int J Oncol 35(6):1449–1462
Frankel SR (2003) Oblimersen sodium (G3139 Bcl-2 antisense oligonucleotide) therapy in Waldenstrom's macroglobulinemia: a targeted approach to enhance apoptosis. Semin Oncol 30(2):300–304
Baell JB, Huang DC (2002) Prospects for targeting the Bcl-2 family of proteins to develop novel cytotoxic drugs. Biochem Pharmacol 64(5–6):851–863
Kutzki O et al (2002) Development of a potent Bcl-x(L) antagonist based on alpha-helix mimicry. J Am Chem Soc 124(40):11838–11839
Becattini B et al (2004) Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-X(L). Chem Biol 11(3):389–395
Qian J et al (2004) Discovery of novel inhibitors of Bcl-xL using multiple high-throughput screening platforms. Anal Biochem 328(2):131–138
Vassilev LT et al (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303(5659):844–848
Stoelcker B et al (2000) Tumor necrosis factor induces tumor necrosis via tumor necrosis factor receptor type 1-expressing endothelial cells of the tumor vasculature. Am J Pathol 156(4):1171–1176
LeBlanc HN, Ashkenazi A (2003) Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ 10(1):66–75
Takeda K et al (2001) Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 7(1):94–100
Cretney E et al (2002) Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 168(3):1356–1361
Herbeuval JP et al (2003) Macrophages from cancer patients: analysis of TRAIL, TRAIL receptors, and colon tumor cell apoptosis. J Natl Cancer Inst 95(8):611–621
Cartron G et al (2004) From the bench to the bedside: ways to improve rituximab efficacy. Blood 104(9):2635–2642
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674
Cory S, Huang DC, Adams JM (2003) The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22(53):8590–8607
Plati J, Bucur O, Khosravi-Far R (2011) Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb) 3(4):279–296
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Wagh, A.R., Bose, K. (2019). Apoptosis in Cancer Cell Signaling and Current Therapeutic Possibilities. In: Bose, K., Chaudhari, P. (eds) Unravelling Cancer Signaling Pathways: A Multidisciplinary Approach. Springer, Singapore. https://doi.org/10.1007/978-981-32-9816-3_5
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DOI: https://doi.org/10.1007/978-981-32-9816-3_5
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