Apoptosis and cancer

doi:10.1017/CBO9780511663543.004

3 - Apoptosis and cancer

Published online by Cambridge University Press: 03 March 2010

Gerard Evan and

Edited by

Alex E. MacKenzie and

Robert G. Korneluk

Show author details

Erinn L. Soucie: Affiliation:
Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada
Gerard Evan: Affiliation:
Cancer Research Institute, University of California San Francisco, San Francisco, USA
Linda Z. Penn: Affiliation:
Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada
Martin Holcik: Affiliation:
University of Ottawa
Eric C. LaCasse: Affiliation:
University of Ottawa
Alex E. MacKenzie: Affiliation:
University of Ottawa
Robert G. Korneluk: Affiliation:
University of Ottawa

Book contents

Get access

Summary

Introduction

The body of knowledge concerning apoptosis and the molecular mechanisms involved in this cellular process continues to expand at an unprecedented rate. This knowledge has impacted not only on our understanding of cancer development, but also on diagnosis and treatment approaches for malignant diseases. This chapter summarizes some of the ways in which tumor cells have successfully corrupted cell survival and death machinery in order to evade the penalty of apoptosis. This is followed by a discussion of novel therapeutics that have begun to emerge and which are designed to address directly these mechanistic changes that can confound current treatment regimens. The advent of current technologies such as laser capture micro-dissection of tumor tissues and microarray expression profiling have also allowed for accurate diagnosis of cancer genotypes. With these and other technologies, the potential now exists to develop new treatment regimens that can directly target individual tumor susceptibilities and, further, to predict the likelihood of response of a particular tumor to specific treatments. Together, advances in the field of apoptosis research have resulted in a revolution in the design of novel anti-cancer therapeutics for cancer treatment. In future, diagnosis of the nature of the anti-apoptotic lesions within a given tumor cell could be directly translated into a rational treatment strategy to eradicate cancers.

Defining cancer in apoptotic terms

The word “cancer” has evolved to become an umbrella term which encompasses the many incarnations of the disease.

Type: Chapter
Information: Apoptosis in Health and Disease
Clinical and Therapeutic Aspects
, pp. 75 - 95

DOI: https://doi.org/10.1017/CBO9780511663543.004 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2005

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Adida, C., Crotty, P. L., McGrath, J., Berrebi, D., Diebold, J., and Altieri, D. C. (1998). Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am. J. Pathol., 152, 43–9Google Scholar PubMed

Altieri, D. C. (2003). Validating survivin as a cancer therapeutic target. Nat. Rev. Cancer, 3, 46–54CrossRef Google Scholar PubMed

Blohm, D. H. and Guiseppi-Elie, A. (2001). New developments in microarray technology. Curr. Opin. Biotechnol., 12, 41–7CrossRef Google Scholar PubMed

Bottger, A., Bottger, V., Sparks, A., Liu, W. L., Howard, S. F., and Lane, D. P. (1997). Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo. Curr. Biol., 7, 860–9CrossRef Google Scholar PubMed

Boxer, L. M. and Dang, C. V. (2001). Translocations involving c-myc and c-myc function. Oncogene, 20, 5595–610CrossRef Google Scholar PubMed

Butler, L. M., Agus, D. B., Scher, H. I.et al. (2000). Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res., 60, 5165–70Google Scholar PubMed

Chen, J., Wu, W., Tahir, S. K.et al. (2000). Down-regulation of survivin by antisense oligonucleotides increases apoptosis, inhibits cytokinesis and anchorage-independent growth. Neoplasia, 2, 235–41CrossRef Google Scholar PubMed

Cheng, E. H., Wei, M. C., Weiler, S.et al. (2001). BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell, 8, 705–11CrossRef Google Scholar PubMed

Chittenden, T. (2002). BH3 domains: intracellular death-ligands critical for initiating apoptosis. Cancer Cell, 2, 165–6CrossRef Google Scholar PubMed

Cho, H., Mu, J., Kim, J. K.et al. (2001). Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science, 292, 1728–31CrossRef Google Scholar

Collins, M. K., Perkins, G. R., Rodriguez-Tarduchy, G., Nieto, M. A., and Lopez-Rivas, A. (1994). Growth factors as survival factors: regulation of apoptosis. Bioessays, 16, 133–8CrossRef Google Scholar PubMed

Coultas, L. and Strasser, A. (2003). The role of the Bcl-2 protein family in cancer. Semin. Cancer Biol., 13, 115–23CrossRef Google Scholar

Darnell, J. E. Jr. (2002). Transcription factors as targets for cancer therapy. Nat. Rev. Cancer, 2, 740–9CrossRef Google Scholar PubMed

Datta, S. R., Brunet, A., and Greenberg, M. E. (1999). Cellular survival: a play in three Akts. Genes Dev., 13, 2905–27CrossRef Google Scholar PubMed

Dou, Q. P. and Li, B. (1999). Proteasome inhibitors as potential novel anticancer agents. Drug Resist. Update, 2, 215–23CrossRef Google Scholar PubMed

Drevs, J., Medinger, M., Schmidt-Gersbach, C., Weber, R., and Unger, C. (2003). Receptor tyrosine kinases: the main targets for new anticancer therapy. Curr. Drug Targets, 4, 113–21CrossRef Google Scholar PubMed

Eischen, C. M., Rehg, J. E., Korsmeyer, S. J., and Cleveland, J. L. (2002). Loss of Bax alters tumor spectrum and tumor numbers in ARF-deficient mice. Cancer Res., 62, 2184–91Google Scholar PubMed

Elenbaas, B., Spirio, L., Koerner, F.et al. (2001). Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev., 15, 50–65CrossRef Google Scholar PubMed

Elliott, K., Ge, K., Du, W., and Prendergast, G. C. (2000). The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program. Oncogene, 19, 4669–84CrossRef Google Scholar PubMed

Evan, G. I. and Vousden, K. H. (2001). Proliferation, cell cycle and apoptosis in cancer. Nature, 411, 342–8CrossRef Google Scholar

Fisher, M. J., Virmani, A. K., Wu, L.et al. (2001). Nucleotide substitution in the ectodomain of trail receptor DR4 is associated with lung cancer and head and neck cancer. Clin. Cancer Res., 7, 1688–97Google Scholar PubMed

Foster, B. A., Coffey, H. A., Morin, M. J., and Rastinejad, F. (1999). Pharmacological rescue of mutant p53 conformation and function. Science, 286, 2507–10CrossRef Google Scholar PubMed

Gelmetti, V., Zhang, J., Fanelli, M., Minucci, S., Pelicci, P. G., and Lazar, M. A. (1998). Aberrant recruitment of the nuclear receptor corepressor–histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol. Cell Biol., 18, 7185–91CrossRef Google Scholar PubMed

Gilmore, T., Gapuzan, M. E., Kalaitzidis, D., and Starczynowski, D. (2002). Rel/NF-kappa B/I kappa B signal transduction in the generation and treatment of human cancer. Cancer Lett., 181, 1–9CrossRef Google Scholar PubMed

Glaser, K. B., Staver, M. J., Waring, J. F., Stender, J., Ulrich, R. G., and Davidsen, S. K. (2003). Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol. Cancer Ther., 2, 151–63Google Scholar PubMed

Gross, A., McDonnell, J. M., and Korsmeyer, S. J. (1999). BCL-2 family members and the mitochondria in apoptosis. Genes Dev., 13, 1899–911CrossRef Google Scholar PubMed

Guidez, F., Petrie, K., Ford, A. M.et al. (2000). Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein. Blood, 96, 2557–61Google Scholar PubMed

Gutierrez-Puente, Y., Zapata-Benavides, P., Tari, A. M., and Lopez-Berestein, G. (2002). Bcl-2-related antisense therapy. Semin. Oncol., 29, 71–6Google Scholar PubMed

Hanahan, D. and Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57–70CrossRef Google Scholar PubMed

Harada, K., Toyooka, S., Shivapurkar, N.et al. (2002). Deregulation of caspase 8 and 10 expression in pediatric tumors and cell lines. Cancer Res., 62, 5897–901Google Scholar PubMed

Hill, M. M. and Hemmings, B. A. (2002). Inhibition of protein kinase B/Akt. Implications for cancer therapy. Pharmacol. Ther., 93, 243–51CrossRef Google Scholar PubMed

Holmes-McNary, M. and Baldwin, A. S. Jr. (2000). Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IkappaB kinase. Cancer Res., 60, 3477–83Google Scholar PubMed

Hopkins-Donaldson, S., Bodmer, J. L., Bourloud, K. B., Brognara, C. B., Tschopp, J., and Gross, N. (2000). Loss of caspase-8 expression in highly malignant human neuroblastoma cells correlates with resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res., 60, 4315–19Google Scholar PubMed

Hu, S., Vincenz, C., Buller, M., and Dixit, V. M. (1997). A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis. J. Biol. Chem., 272, 9621–4CrossRef Google Scholar PubMed

Irmler, M., Thome, M., Hahne, M.et al. (1997). Inhibition of death receptor signals by cellular FLIP. Nature, 388, 190–5CrossRef Google Scholar PubMed

Ishizaki, Y., Cheng, L., Mudge, A. W., and Raff, M. C. (1995). Programmed cell death by default in embryonic cells, fibroblasts, and cancer cells. Mol. Biol. Cell, 6, 1443–58CrossRef Google Scholar PubMed

Karin, M., Cao, Y., Greten, F. R., and Li, Z. W. (2002). NF-kappaB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer, 2, 301–10CrossRef Google Scholar PubMed

Kasof, G. M. and Gomes, B. C. (2001). Livin, a novel inhibitor of apoptosis protein family member. J. Biol. Chem., 276, 3238–46CrossRef Google Scholar PubMed

Khan, M. M., Nomura, T., Kim, H.et al. (2001). Role of PML and PML-RARalpha in Mad-mediated transcriptional repression. Mol. Cell, 7, 1233–43CrossRef Google Scholar PubMed

Khwaja, A., Rodriguez-Viciana, P., Wennstrom, S., Warne, P. H., and Downward, J. (1997). Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J., 16, 2783–93CrossRef Google Scholar PubMed

Knudson, C. M., Johnson, G. M., Lin, Y., and Korsmeyer, S. J. (2001). Bax accelerates tumorigenesis in p53-deficient mice. Cancer Res., 61, 659–65Google Scholar PubMed

Krajewska, M., Moss, S. F., Krajewski, S., Song, K., Holt, P. R., and Reed, J. C. (1996). Elevated expression of Bcl-X and reduced Bak in primary colorectal adenocarcinomas. Cancer Res., 56, 2422–7Google Scholar

Lakhani, S. R. and Ashworth, A. (2001). Microarray and histopathological analysis of tumors: the future and the past?Nat. Rev. Cancer, 1, 151–7CrossRef Google Scholar PubMed

Lee, S. H., Shin, M. S., Kim, H. S.et al. (2001). Somatic mutations of TRAIL-receptor 1 and TRAIL-receptor 2 genes in non-Hodgkin's lymphoma. Oncogene, 20, 399–403CrossRef Google Scholar PubMed

Letai, A., Bassik, M. C., Walensky, L. D., Sorcinelli, M. D., Weiler, S., and Korsmeyer, S. J. (2002). Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell, 2, 183–92CrossRef Google Scholar PubMed

Lewis, J., Devin, A., Miller, A.et al. (2000). Disruption of hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-kappaB activation. J. Biol. Chem., 275, 10519–26CrossRef Google Scholar

Lorenzo, H. K., Susin, S. A., Penninger, J., and Kroemer, G. (1999). Apoptosis inducing factor (AIF): a phylogenetically old, caspase-independent effector of cell death. Cell Death Differ., 6, 516–24CrossRef Google Scholar PubMed

Mariadason, J. M., Corner, G. A., and Augenlicht, L. H. (2000). Genetic reprogramming in pathways of colonic cell maturation induced by short chain fatty acids: comparison with trichostatin A, sulindac, and curcumin and implications for chemoprevention of colon cancer. Cancer Res., 60, 4561–72Google Scholar PubMed

Meijerink, J. P., Mensink, E. J., Wang, K.et al. (1998). Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood, 91, 2991–7Google Scholar PubMed

Mueller, C. M. and Scott, D. W. (2000). Distinct molecular mechanisms of Fas resistance in murine B lymphoma cells. J. Immunol., 165, 1854–62CrossRef Google Scholar PubMed

Muschen, M., Warskulat, U., and Beckmann, M. W. (2000). Defining CD95 as a tumor suppressor gene. J. Mol. Med., 78, 312–25CrossRef Google Scholar PubMed

Nimmanapalli, R. and Bhalla, K. (2002). Novel targeted therapies for Bcr-Abl-positive acute leukemias: beyond STI571. Oncogene, 21, 8584–90CrossRef Google Scholar PubMed

Olson, M. and Kornbluth, S. (2001). Mitochondria in apoptosis and human disease. Curr. Mol. Med., 1, 91–122CrossRef Google Scholar PubMed

Ozoren, N., Fisher, M. J., Kim, K.et al. (2000). Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance. Int. J. Oncol., 16, 917–25Google Scholar

Pandey, P., Saleh, A., Nakazawa, A.et al. (2000). Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J., 19, 4310–22CrossRef Google Scholar PubMed

Pelengaris, S., Rudolph, B., and Littlewood, T. (2000). Action of Myc in vivo – proliferation and apoptosis. Curr. Opin. Genet. Dev., 10, 100–5CrossRef Google Scholar PubMed

Perez, D. and White, E. (2003). E1A sensitizes cells to tumor necrosis factor alpha by downregulating c-FLIP S. J. Virol., 77, 2651–62CrossRef Google Scholar PubMed

Prendergast, G. C. (1999). Mechanisms of apoptosis by c-Myc. Oncogene, 18, 2967–87CrossRef Google Scholar PubMed

Pruschy, M., Rocha, S., Zaugg, K.et al. (2001). Key targets for the execution of radiation-induced tumor cell apoptosis: the role of p53 and caspases. Int. J. Radiat. Oncol. Biol. Phys., 49, 561–7CrossRef Google Scholar PubMed

Puthalakath, H. and Strasser, A. (2002). Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ., 9, 505–12CrossRef Google Scholar PubMed

Rampino, N., Yamamoto, H., Ionov, Y.et al. (1997). Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science, 275, 967–9CrossRef Google Scholar PubMed

Ravagnan, L., Roumier, T., and Kroemer, G. (2002). Mitochondria, the killer organelles and their weapons. J. Cell Physiol., 192, 131–7CrossRef Google Scholar PubMed

Richmond, A. (2002). Nf-kappa B, chemokine gene transcription and tumor growth. Nat. Rev. Immunol., 2, 664–74CrossRef Google Scholar

Richon, V. M., Emiliani, S., Verdin, E.et al. (1998). A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc. Natl. Acad. Sci. USA, 95, 3003–7CrossRef Google Scholar PubMed

Rossi, A., Kapahi, P., Natoli, G.et al. (2000). Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature, 403, 103–8CrossRef Google Scholar PubMed

Rudner, J., Jendrossek, V., and Belka, C. (2002). New insights in the role of Bcl-2: Bcl-2 and the endoplasmic reticulum. Apoptosis, 7, 441–7CrossRef Google Scholar PubMed

Sato, S., Fujita, N., and Tsuruo, T. (2000). Modulation of Akt kinase activity by binding to Hsp90. Proc. Natl. Acad. Sci. USA, 97, 10832–7CrossRef Google Scholar PubMed

Seitz, S., Wassmuth, P., Fischer, J.et al. (2002). Mutation analysis and mRNA expression of trail-receptors in human breast cancer. Int. J. Cancer, 102, 117–28CrossRef Google Scholar PubMed

Shi, Y. (2002). Mechanisms of caspase activation and inhibition during apoptosis. Mol. Cell, 9, 459–70CrossRef Google Scholar PubMed

Shibata, M. A., Liu, M. L., Knudson, M. C.et al. (1999). Haploid loss of bax leads to accelerated mammary tumor development in C3(1)/SV40-TAg transgenic mice: reduction in protective apoptotic response at the preneoplastic stage. EMBO J., 18, 2692–701CrossRef Google Scholar PubMed

Shin, M. S., Kim, H. S., Lee, S. H.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, 4942–6Google Scholar

Simon, R., Radmacher, M. D., Dobbin, K., and McShane, L. M. (2003). Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification. J. Natl. Cancer Inst., 95, 14–18CrossRef Google Scholar PubMed

Skorski, T. (2002). Oncogenic tyrosine kinases and the DNA-damage response. Nat. Rev. Cancer, 2, 351–60CrossRef Google Scholar PubMed

Skorski, T., Bellacosa, A., Nieborowska-Skorska, M.et al. (1997). Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J., 16, 6151–61CrossRef Google Scholar PubMed

Smyth, M. J., Takeda, K., Hayakawa, Y., Peschon, J. J., Brink, M. R., and Yagita, H. (2003). Nature's TRAIL – on a path to cancer immunotherapy. Immunity, 18, 1–6CrossRef Google Scholar PubMed

Soengas, M. S., Capodieci, P., Polsky, D.et al. (2001). Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature, 409, 207–11CrossRef Google Scholar PubMed

Sporn, M. B., Suh, N., and Mangelsdorf, D. J. (2001). Prospects for prevention and treatment of cancer with selective PPARgamma modulators (SPARMs). Trends Mol. Med., 7, 395–400CrossRef Google Scholar

Teitz, T., Lahti, J. M., and Kidd, V. J. (2001). Aggressive childhood neuroblastomas do not express caspase-8: an important component of programmed cell death. J. Mol. Med., 79, 428–36CrossRef Google Scholar

Teitz, T., Wei, T., Valentine, M. B.et al. (2000). Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat. Med., 6, 529–35CrossRef Google Scholar PubMed

Tepper, C. G. and Seldin, M. F. (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, 1727–37Google Scholar PubMed

Thome, M., Schneider, P., Hofmann, K.et al. (1997). Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature, 386, 517–21CrossRef Google Scholar PubMed

Timmer, T., Vries, E. G., and Jong, S. (2002). Fas receptor-mediated apoptosis: a clinical application?J. Pathol., 196, 125–34CrossRef Google Scholar PubMed

West, K. A., Sianna Castillo, S., and Dennis, P. A. (2002). Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist. Update, 5, 234–48CrossRef Google Scholar PubMed

Wong, W. W., Dimitroulakos, J., Minden, M. D., and Penn, L. Z. (2002). HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia, 16, 508–19CrossRef Google Scholar PubMed

Yamasaki, L. (1999). Balancing proliferation and apoptosis in vivo: the Goldilocks theory of E2F/DP action. Biochim. Biophys. Acta, 1423, M9–15Google Scholar PubMed