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Review
. 2011;111:39-96.
doi: 10.1016/B978-0-12-385524-4.00002-7.

The Essential Role of Evasion From Cell Death in Cancer

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Free PMC article
Review

The Essential Role of Evasion From Cell Death in Cancer

Gemma L Kelly et al. Adv Cancer Res. .
Free PMC article

Abstract

The link between evasion of apoptosis and the development of cellular hyperplasia and ultimately cancer is implicitly clear if one considers how many cells are produced each day and, hence, how many cells must die to make room for the new ones (reviewed in Raff, 1996). Furthermore, cells are frequently experiencing noxious stimuli that can cause lesions in their DNA and faults in DNA replication can occur during cellular proliferation. Such DNA damage needs to be repaired efficiently or cells with irreparable damage must be killed to prevent subsequent division of aberrant cells that may fuel tumorigenesis (reviewed in Weinberg, 2007). The detection of genetic lesions in human cancers that activate prosurvival genes or disable proapoptotic genes have provided the first evidence that defects in programmed cell death can cause cancer (Tagawa et al., 2005; Tsujimoto et al., 1984; Vaux, Cory, and Adams, 1988) and this concept was proven by studies with genetically modified mice (Egle et al., 2004b; Strasser et al., 1990a). It is therefore now widely accepted that evasion of apoptosis is a requirement for both neoplastic transformation and sustained growth of cancer cells (reviewed in Cory and Adams, 2002; Hanahan and Weinberg, 2000; Weinberg, 2007). Importantly, apoptosis is also a major contributor to anticancer therapy-induced killing of tumor cells (reviewed in Cory and Adams, 2002; Cragg et al., 2009). Consequently, a detailed understanding of apoptotic cell death will help to better comprehend the complexities of tumorigenesis and should assist with the development of improved targeted therapies for cancer based on the direct activation of the apoptotic machinery (reviewed in Lessene, Czabotar, and Colman, 2008).

Figures

Figure 1
Figure 1. Diagrammatic representation of the two pathways leading to apoptosis induction
The “Bcl-2 family regulated” apoptotic pathway is initiated by cytotoxic stimuli, including DNA damaging agents and cytokine withdrawal, which perturb the balance between pro-survival and pro-apoptotic Bcl-2 family proteins within the cell, leading to activation of the downstream caspase cascade and ultimately apoptosis. The Bcl-2 family of proteins consists of the pro-apoptotic BH3-only proteins (including Bim, Bad, tBid, Hrk, Bmf, Bik, Puma and Noxa), the pro-survival Bcl-2 proteins (including Bcl-2, Bcl-xL, Bcl-w, Mcl-1, A1 and Boo/Diva) and the pro-apoptotic executioner proteins (Bax, Bak and possibly also Bok). Signaling via the intrinsic pathway leads to the activation of the BH3-only proteins, by either transcriptional or post-translational mechanisms, allowing the BH3-only proteins to engage the Bcl-2 pro-survival proteins, thereby releasing Bax and Bak to induce mitochondrial outer membrane permeabilization (MOMP). The subsequent release of cytochrome c from the mitochondrial outer membrane, together with Apaf-1 and dATP, forms the apoptosome leading to the activation of the initiator caspase, caspase-9 and the activation of downstream activator caspases-3, -6, -7, which proteolyze hundreds of cellular proteins and result in the destruction of the cell. The “death receptor” pathway is initiated by the engagement of death receptors at the cell membrane that signal via the adaptor protein FADD to activate the initiator caspase, caspase-8, leading to activation of the effector caspases, caspases-3, -6 and -7 and apoptosis induction. The “death receptor” pathway can engage the “Bcl-2 family regulated” pathway through caspase-8 mediated cleavage and activation of the BH3-only protein Bid to tBid, which can then bind and sequester the Bcl-2 pro-survival proteins and/or directly activate Bax/Bak.
Figure 2
Figure 2. Binding specificities of the BH3-only proteins for the Bcl-2 pro-survival proteins
The BH3-only proteins Bim, Puma and tBid are capable of binding all of the Bcl-2 pro-survival proteins (so-called “promiscuous” binders) whereas Bad, Hrk, Blk, and Bmf can only bind to Bcl-2, Bcl-xL and Bcl-w and Noxa can only bind to Mcl-1 and A1 (so-called “selective” binders).
Figure 3
Figure 3. Functions of the pro-survival Bcl-2 proteins in the lymphoid and myeloid lineages
The stages of lymphoid and myeloid differentiation from progenitor hematopoietic stem cells (HSCs) emerging in the bone marrow to fully differentiated cells circulating throughout the periphery are shown diagrammatically. In the bone marrow, HSCs differentiate into multipotent progenitors (MPPs) that further differentiate into either common myeloid progenitor (CMPs) capable of maturing via megakaryocyte/erythroid progenitors (MEPs) or granulocyte/monocyte progenitors (GMPs) into mature erythrocytes, megakaryocytes, platelets, neutrophils, eosinophils and macrophages or into common lymphoid progenitor (CLPs) capable of generating mature T and B cells. T cell development occurs mainly in the thymus where cells differentiate through four stages of CD4CD8 double negative (DN) thymocytes to develop via immature CD4+CD8+ DP thymocytes into mature CD8+ or CD4+ single positive thymocytes, leading to the emergence of mature T cells in the periphery that can become activated upon TCR engagement. The development of immature B cells from CLPs occurs within the bone marrow with mature B cells emerging into the periphery where upon meeting cognate antigen they can migrate to form germinal centres (GCs) and further differentiate into memory B or antigen secreting plasma cells. Marked in block arrows are the stages of differentiation at which the different Bcl-2 pro-survival proteins are required for survival, as determined from experiments with gene-targeted mice. The dashed arrows indicate i) a role for Mcl-1 only when macrophages are challenged with apoptotic stimuli and ii) the inference that A1 is important in activated T cells on the basis that A1 is up-regulated following TCR engagement.
Figure 4
Figure 4. Incidence of amplification and deletion peaks involving the Bcl-2 family members in human cancers (taken from (Beroukhim et al., 2010))
A. Table to show the frequency of chromosomal deletions or amplifications affecting the pro-survival and pro-apoptotic Bcl-2 family members relative to non-Bcl-2 family members in 3131 human cancer samples of 26 different tumor types. B. Copy number profiles of locations on chromosome 1 around the mcl1 gene in 50 cancer samples including those from lung, breast, neural, gastrointestinal and sarcomas.
Figure 5
Figure 5. Expression levels of the bcl-2 pro-survival genes in lymphoid and myeloid-derived human malignancies
The box and whisker plots summarize the relative expression levels (median value is the red line, lower and upper quartiles represented by the box and the distribution of the data shown by the whiskers) of the bcl-2 pro-survival genes, a1, bcl-2, bcl-xL and mcl-1 in primary B-ALL (n=925), T-ALL (n=68), B-CLL (n=101), AML (n=322), Plasma cell leukemia (n=6), Myeloma (n=102), B-cell lymphoma (n=198), Burkitt lymphoma (n=36) and T-cell lymphoma (n=43) patients. The data have been generated from the GeneSapiens database as described in (Kilpinen et al., 2008), which is a database of the human transriptome based on data generated from Affymetrix arrays.
Figure 6
Figure 6. Crystal structures of BHRF1 and Bcl-xL in complex with the Bim BH3 peptide (taken from (Kvansakul et al., 2010))
A. The structure of BHRF1 (blue) with the helices labeled a1, a1′, a2-8, is shown in complex with the Bim BH3 domain (yellow). The helices a3-5 of BHRF1 form a hydrophobic binding groove into which the BH3 domain of Bim can bind. D. The comparable structure of Bcl-xL (cyan) with helices labeled a1-8 bound to the BH3 domain of Bim (yellow).

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