Mitochondria: gatekeepers of response to chemotherapy
2013; Elsevier BV; Volume: 23; Issue: 12 Linguagem: Inglês
10.1016/j.tcb.2013.08.003
ISSN1879-3088
AutoresKristopher A. Sarosiek, Tríona Ní Chonghaile, Anthony Letai,
Tópico(s)Cancer, Hypoxia, and Metabolism
Resumo•Mitochondrial apoptotic priming determines cellular response to chemotherapy.•The chemotherapeutic window is based on differential levels of mitochondrial priming.•Mitochondrial priming can be modulated to improve chemotherapy response. Mitochondria are cellular organelles that regulate commitment to and execution of apoptosis. The intrinsic apoptotic pathway culminates in the permeabilization of the mitochondrial outer membrane and dismantling of the cell. Apoptosis of cancer cells is a favorable outcome when administering chemotherapeutic treatment, yet the basis for why some cancers are sensitive to chemotherapy whereas others are not has historically been poorly understood. In this review, we present recent work that has demonstrated the importance of mitochondrial apoptotic priming, or how close a cell is to the threshold of apoptosis, in determining whether a cell will undergo apoptosis after chemotherapy treatment. Differential levels of apoptotic priming in tumors create bona fide opportunities and challenges for effective use of targeted and cytotoxic chemotherapies. Mitochondria are cellular organelles that regulate commitment to and execution of apoptosis. The intrinsic apoptotic pathway culminates in the permeabilization of the mitochondrial outer membrane and dismantling of the cell. Apoptosis of cancer cells is a favorable outcome when administering chemotherapeutic treatment, yet the basis for why some cancers are sensitive to chemotherapy whereas others are not has historically been poorly understood. In this review, we present recent work that has demonstrated the importance of mitochondrial apoptotic priming, or how close a cell is to the threshold of apoptosis, in determining whether a cell will undergo apoptosis after chemotherapy treatment. Differential levels of apoptotic priming in tumors create bona fide opportunities and challenges for effective use of targeted and cytotoxic chemotherapies. A longstanding question among not only patients but also the oncologists that are treating them is ‘why does chemotherapy work?’ This important question is asked because chemotherapy does, at times, work impressively well, leading to long-term cures of otherwise fatal neoplasms. However, despite growing understanding of how cancers arise, grow, metastasize, and eventually overcome the host, the mechanisms behind successful treatment of cancers are poorly understood [1Rich T. et al.Defying death after DNA damage.Nature. 2000; 407: 777-783Crossref PubMed Scopus (590) Google Scholar, 2Fulda S. Debatin K-M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.Oncogene. 2006; 25: 4798-4811Crossref PubMed Scopus (1779) Google Scholar]. The key determinants of response to chemotherapy are explored in this review, with a focus on how the pathway of mitochondrial apoptosis affects treatment outcome. Treatment of human malignancies with chemotherapy with curative intent has been successfully conducted for over 50 years, with millions of cancer survivors enjoying long lives after treatment [3De Moor J.S. et al.Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care.Cancer Epidemiol. Biomarkers Prev. 2013; 22: 561-570Crossref PubMed Scopus (508) Google Scholar]. However, millions more have succumbed to their disease. Regardless of whether they are considered ‘cytotoxic’ or ‘targeted’, most chemotherapies function by inducing a form of irreversible programmed cell death called apoptosis [4Johnstone R.W. et al.Apoptosis: a link between cancer genetics and chemotherapy.Cell. 2002; 108: 153-164Abstract Full Text Full Text PDF PubMed Scopus (2031) Google Scholar, 5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Crossref PubMed Scopus (425) Google Scholar, 6Kaufmann S.H. Earnshaw W.C. Induction of apoptosis by cancer chemotherapy.Exp. Cell Res. 2000; 256: 42-49Crossref PubMed Scopus (1082) Google Scholar, 7Sarosiek K.A. et al.BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response.Mol. Cell. 2013; 51https://doi.org/10.1016/j.molcel.2013.08.047Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. Apoptosis can proceed via two distinct pathways: intrinsic and extrinsic [8Tait S.W.G. Green D.R. Mitochondria and cell death: outer membrane permeabilization and beyond.Nat. Rev. Mol. Cell Biol. 2010; 11: 621-632Crossref PubMed Scopus (1905) Google Scholar]. The extrinsic apoptotic pathway is engaged on activation of cell surface death receptors and has a limited, controversial role in chemotherapy-induced apoptosis [2Fulda S. Debatin K-M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.Oncogene. 2006; 25: 4798-4811Crossref PubMed Scopus (1779) Google Scholar, 4Johnstone R.W. et al.Apoptosis: a link between cancer genetics and chemotherapy.Cell. 2002; 108: 153-164Abstract Full Text Full Text PDF PubMed Scopus (2031) Google Scholar, 6Kaufmann S.H. Earnshaw W.C. Induction of apoptosis by cancer chemotherapy.Exp. Cell Res. 2000; 256: 42-49Crossref PubMed Scopus (1082) Google Scholar]. We therefore focus solely on the intrinsic, or mitochondrial, apoptotic pathway in this review. Mitochondrial apoptosis is controlled by the pro- and antiapoptotic proteins of the BCL-2 family, which can be divided into three categories based on their intracellular function and sequence homology (reviewed in [9Chipuk J.E. et al.The BCL-2 family reunion.Mol. Cell. 2010; 37: 299-310Abstract Full Text Full Text PDF PubMed Scopus (1192) Google Scholar]). One category includes the antiapoptotic proteins BCL-2, BCL-w, MCL-1, BFL-1, and BCL-XL, which contain all four BCL-2 homology domains (BH1–4). These proteins prevent apoptosis by binding and sequestering their proapoptotic counterparts. The second category, the BH3-only proteins, includes the proapoptotic proteins PUMA, BIM, BID, BAD, BIK, NOXA, and BMF, which contain only the BH3 domain. The final category, the effectors, contains BAX and BAK, which contain domains BH1–3 and can be activated by a subset of BH3-only proteins that includes BIM, BID, and, potentially, PUMA [10Czabotar P.E. et al.Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis.Cell. 2013; 152: 519-531Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 11Kim H. et al.Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies.Nat. Cell Biol. 2006; 8: 1348-1358Crossref PubMed Scopus (710) Google Scholar, 12Leshchiner E.S. et al.Direct activation of full-length proapoptotic BAK.Proc. Natl. Acad. Sci. 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It had been suggested that BAX and BAK are activated not by BIM and BID but instead via the inactivation of antiapoptotic BCL-2 family members [17Willis S.N. et al.Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak.Science. 2007; 315: 856-859Crossref PubMed Scopus (944) Google Scholar]. However, recent studies have confirmed the direct binding and activation of BAX by BIM and BAK by BID [10Czabotar P.E. et al.Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis.Cell. 2013; 152: 519-531Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, 14Gavathiotis E. et al.BAX activation is initiated at a novel interaction site.Nature. 2008; 455: 1076-1081Crossref PubMed Scopus (565) Google Scholar, 18Moldoveanu T. et al.BID-induced structural changes in BAK promote apoptosis.Nat. Struct. Mol. Biol. 2013; https://doi.org/10.1038/nsmb.2563Crossref PubMed Scopus (162) Google Scholar]. Furthermore, although both BIM and BID are able to activate either of the effectors, BIM preferentially activates BAX while BID preferentially activates BAK [7Sarosiek K.A. et al.BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response.Mol. Cell. 2013; 51https://doi.org/10.1016/j.molcel.2013.08.047Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. On activation, BAK and BAX oligomerize and directly cause mitochondrial outer membrane permeabilization (MOMP), a critical event during apoptosis. Cytochrome c and other factors are released after MOMP and associate with several cytosolic proteins including APAF-1 to activate caspases for dismantling of the cell [8Tait S.W.G. Green D.R. Mitochondria and cell death: outer membrane permeabilization and beyond.Nat. Rev. Mol. Cell Biol. 2010; 11: 621-632Crossref PubMed Scopus (1905) Google Scholar]. Even in the absence of caspase activation, post-MOMP mitochondria are progressively impaired in their ability to generate ATP and cannot maintain cellular survival except in specific, non-physiological circumstances [8Tait S.W.G. Green D.R. Mitochondria and cell death: outer membrane permeabilization and beyond.Nat. Rev. Mol. Cell Biol. 2010; 11: 621-632Crossref PubMed Scopus (1905) Google Scholar, 19Colell A. et al.GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation.Cell. 2007; 129: 983-997Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, 20Lartigue L. et al.Caspase-independent mitochondrial cell death results from loss of respiration, not cytotoxic protein release.Mol. Biol. Cell. 2009; 20: 4871-4884Crossref PubMed Scopus (90) Google Scholar]. MOMP can thus be considered the ‘point of no return’ in mitochondrial apoptosis. MOMP, and consequent apoptosis, is triggered clinically when a chemotherapeutic agent induces a sufficient amount of stress within a cancer cell by damaging critical cellular components such as microtubules, DNA, or key signaling pathways [2Fulda S. Debatin K-M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.Oncogene. 2006; 25: 4798-4811Crossref PubMed Scopus (1779) Google Scholar, 4Johnstone R.W. et al.Apoptosis: a link between cancer genetics and chemotherapy.Cell. 2002; 108: 153-164Abstract Full Text Full Text PDF PubMed Scopus (2031) Google Scholar, 6Kaufmann S.H. Earnshaw W.C. Induction of apoptosis by cancer chemotherapy.Exp. Cell Res. 2000; 256: 42-49Crossref PubMed Scopus (1082) Google Scholar]. The cell responds by unleashing proapoptotic proteins or downregulating antiapoptotic members of the BCL-2 family, either of which can lead to a shift in the life/death balance in the cell irreversibly towards destruction [4Johnstone R.W. et al.Apoptosis: a link between cancer genetics and chemotherapy.Cell. 2002; 108: 153-164Abstract Full Text Full Text PDF PubMed Scopus (2031) Google Scholar, 6Kaufmann S.H. Earnshaw W.C. Induction of apoptosis by cancer chemotherapy.Exp. Cell Res. 2000; 256: 42-49Crossref PubMed Scopus (1082) Google Scholar, 7Sarosiek K.A. et al.BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response.Mol. Cell. 2013; 51https://doi.org/10.1016/j.molcel.2013.08.047Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. Based on this understanding, both the state of the BCL-2 family of apoptosis-regulating proteins in the cell before encountering the stress and the magnitude of the dynamic response to the stress can have a profound impact on the eventual fate of the cell. These concepts are explored further below. Regulation of the balance of pro- and antiapoptotic proteins within cells, and thus how close a cell is to the threshold of apoptosis, is dependent on many factors. To avoid apoptosis, a cell must express a sufficient amount of antiapoptotic proteins to bind and inactivate what proapoptotic counterparts are also present. Furthermore, most cells contain an additional amount of ‘buffering’ antiapoptotic proteins that can inactivate further pro-death signals that are encountered on a stochastic basis under normal, physiological conditions [5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Crossref PubMed Scopus (425) Google Scholar]. The amount of buffering that a cell may employ varies by the type of cell; many cells in the hematopoietic and immune systems maintain relatively small buffers of antiapoptotic proteins [5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Crossref PubMed Scopus (425) Google Scholar], probably to enable their quick and efficient elimination as the need arises [21Opferman J.T. Korsmeyer S.J. Apoptosis in the development and maintenance of the immune system.Nat. Immunol. 2003; 4: 410-415Crossref PubMed Scopus (415) Google Scholar]. Conversely, cells with a longer lifespan such as the highly specialized, fully differentiated cells that constitute vital organs are more buffered against short-term, stochastic fluctuations in cellular stress [5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Crossref PubMed Scopus (425) Google Scholar] that could erroneously trigger cell death in a vital cell, to the detriment of the host's survival (reviewed in [22Wright K.M. Deshmukh M. Restricting apoptosis for postmitotic cell survival and its relevance to cancer.Cell Cycle. 2006; 5: 1616-1620Crossref PubMed Scopus (30) Google Scholar]). The specific factors that control the level of antiapoptotic buffering within healthy cells are unknown but may involve the epigenetic programming that maintains cell identity [23Sasaki H. Matsui Y. Epigenetic events in mammalian germ-cell development: reprogramming and beyond.Nat. Rev. Genet. 2008; 9: 129-140Crossref PubMed Scopus (659) Google Scholar]. The varying levels of antiapoptotic buffering present within cells can affect the outcome of any event that stresses a cell, including chemotherapy treatment. For instance, a cell may express a very large reserve of unbound antiapoptotic proteins that are available for binding of their proapoptotic counterparts and therefore be protected against even a substantial amount of subsequent pro-death signaling. Alternatively, a cell may express only enough unbound antiapoptotic proteins to just barely keep the proapoptotic proteins in check and would therefore not be protected from even a small stressor. The cell that has a small reserve of unbound antiapoptotic proteins is ‘primed’ for apoptosis whereas the cell that has a large reserve is ‘unprimed’ (Figure 1). Another way to illustrate this dichotomy is to envision two cells, one close to the threshold (cliff's edge) at which apoptosis is triggered whereas the other is far from that threshold. The one closer to the edge is considered primed whereas the other is unprimed. When these two cells are treated with equal doses of chemotherapy (pushed towards the cliff's edge), the primed cell will be more likely to trigger apoptosis than the unprimed cell if their dynamic response to chemotherapy (strength of push towards edge) is equal (Figure 2A) . Although it aids understanding to define priming in this way, priming is measured by a functional test and thus a label of primed or unprimed can be assigned only based on a given cell's response to systematic proapoptotic stimuli as described below.Figure 2Apoptotic priming can affect response to chemotherapy. (A) A cell that is primed for apoptosis is more likely to undergo cell death in response to chemotherapy than an unprimed cell. (B) A cell that is primed for apoptosis nonetheless does not undergo cell death in response to a targeted agent if it does not exhibit dependence on the target of the therapy. A cell that is unprimed but exhibits strong dependence on the target of the therapy may unleash sufficient proapoptotic signaling to trigger apoptosis. (C) Two cells that exhibit similar dependence on the target of the therapy may have different treatment outcomes based on levels of apoptotic priming present in the cells before therapy. (D) A cell that is unprimed yet exhibits dependence on the target of the therapy may become primed in response to the therapy if apoptosis is not triggered directly by the single agent. An additional bolus of proapoptotic signaling, here provided by treatment with a cytotoxic chemotherapy agent that would not kill an unprimed cell, is sufficient to trigger apoptosis.View Large Image Figure ViewerDownload (PPT) Because there may be substantial utility in knowing how close a cancer cell is to the threshold of apoptosis, an assay called BH3 profiling has been developed to measure priming in cancerous and normal cells. The basic principle is to expose mitochondria to peptides derived from the BH3 domains of pro-death BH3-only proteins and measure the resulting magnitude of MOMP (for the full methods, see [24Ryan J. Letai A. BH3 profiling in whole cells by fluorimeter or FACS.Methods. 2013; https://doi.org/10.1016/j.ymeth.2013.04.006Crossref PubMed Scopus (116) Google Scholar]). Heightened sensitivity of mitochondria to BH3 peptides such as BAD BH3 or NOXA BH3, with selective binding to antiapoptotic proteins, might indicate selective dependence on BCL-2 or MCL-1 [25Brunelle J.K. et al.MCL-1-dependent leukemia cells are more sensitive to chemotherapy than BCL-2-dependent counterparts.J. Cell Biol. 2009; 187: 429-442Crossref PubMed Scopus (77) Google Scholar, 26Ryan J. et al.Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 12895-12900Crossref PubMed Scopus (105) Google Scholar, 27Deng J. et al.BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents.Cancer Cell. 2007; 12: 171-185Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar]. Heightened sensitivity to peptides that exhibit promiscuous binding to antiapoptotic proteins, such as BIM BH3 or PUMA BH3, indicates a highly primed state, with a low reserve of unbound antiapoptotic proteins [5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Crossref PubMed Scopus (425) Google Scholar, 27Deng J. et al.BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents.Cancer Cell. 2007; 12: 171-185Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar, 28Davids M.S. et al.Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia.Blood. 2012; 120: 3501-3509Crossref PubMed Scopus (99) Google Scholar, 29Vo T-T. et al.Relative mitochondrial priming of malignant myeloblasts and normal HSCs determines chemotherapeutic success in AML.Cell. 2012; 151: 344-355Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar]. In practice, the assay is typically performed by gently permeabilizing the plasma membrane of cells and adding fixed doses of BH3 peptides derived from the BH3 domain of proapoptotic BH3-only proteins. Mitochondrial potential is then monitored for detection of MOMP, which occurs when the antiapoptotic reserve is exhausted within a cell and BAX and/or BAK are activated (Figure 1). Cells can be labeled as primed or unprimed based on the extent of mitochondrial depolarization (MOMP) that occurs in response to a fixed titration of pro-death BH3 peptides: the faster a cell is depolarized, or the lower concentration of peptide required for MOMP, the more primed it is. Functional assays such as BH3 profiling are critical for the measurement of apoptotic priming within a cell. The activities of the BCL-2 family of proteins are regulated by a plethora of post-translational modifications and interactions with other proteins [30Yip K.W. Reed J.C. Bcl-2 family proteins and cancer.Oncogene. 2008; 27: 6398-6406Crossref PubMed Scopus (728) Google Scholar]. Measuring the expression level of each member of the BCL-2 family, their modifications, and the proteins they are interacting with is not a practical task and, due to additional unknown factors that may modify their activity, may not even provide an accurate assessment of priming and thus creates a need for a function-based assay. By treating a cell with fixed doses of proapoptotic signaling in BH3 profiling, it is possible to measure the integrated functional output of the BCL-2 family efficiently and meaningfully [5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Crossref PubMed Scopus (425) Google Scholar]. Using BH3 profiling to measure levels of apoptotic priming across a range of cancer types, it has been shown that primed cells readily undergo apoptosis in response to cytotoxic chemotherapy whereas unprimed cells are less likely to do so (Table 1) [5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Crossref PubMed Scopus (425) Google Scholar]. Notably, this holds true not only in cancer cell lines but also in primary tumors and can be predictive of how patients will respond to chemotherapy in the clinic [5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Crossref PubMed Scopus (425) Google Scholar, 29Vo T-T. et al.Relative mitochondrial priming of malignant myeloblasts and normal HSCs determines chemotherapeutic success in AML.Cell. 2012; 151: 344-355Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar]. In addition, cells within tumors that have undergone treatment and then recurred are frequently less primed, making them less sensitive to subsequent rounds of chemotherapy [5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Crossref PubMed Scopus (425) Google Scholar, 29Vo T-T. et al.Relative mitochondrial priming of malignant myeloblasts and normal HSCs determines chemotherapeutic success in AML.Cell. 2012; 151: 344-355Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 31Goldsmith K.C. et al.Mitochondrial Bcl-2 family dynamics define therapy response and resistance in neuroblastoma.Cancer Res. 2012; 72: 2565-2577Crossref PubMed Scopus (60) Google Scholar]. The selective pressure of chemotherapy likely culls primed cancer cells, leaving only unprimed cells to repopulate the tumor [5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Crossref PubMed Scopus (425) Google Scholar, 29Vo T-T. et al.Relative mitochondrial priming of malignant myeloblasts and normal HSCs determines chemotherapeutic success in AML.Cell. 2012; 151: 344-355Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar]. These unprimed relapsed tumors are frequently intractable.Table 1Major determinants of chemotherapy success (why chemotherapy works)Drug classTargetExamplesDeterminants of therapy successPrimarySecondaryCancer typeClassical cytotoxic therapyUbiquitous cellular elements (microtubules, DNA, topoisomerases)Paclitaxel (microtubules), topotecan (topoisomerase II), doxorubicin (DNA)Pretreatment mitochondrial apoptotic primingSignaling dynamics post-treatmentMultiple myeloma, ALL, ovarian cancer 5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Crossref PubMed Scopus (425) Google Scholar; CLL 28Davids M.S. et al.Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia.Blood. 2012; 120: 3501-3509Crossref PubMed Scopus (99) Google Scholar; AML 29Vo T-T. et al.Relative mitochondrial priming of malignant myeloblasts and normal HSCs determines chemotherapeutic success in AML.Cell. 2012; 151: 344-355Abstract Full Text Full Text PDF PubMed Scopus (276) Google ScholarTargeted therapyCell specific targets (mutated oncogenes, differentially expressed oncogenes)Erlotinib (EGFR), vemurafenib (V600E), imatinib (BCR-ABL)Presence or absence of targetPretreatment mitochondrial apoptotic priming, signaling dynamics post-treatmentNon-small cell lung cancer 83Lynch T. 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A longstanding misconception is that cancers must ‘disrupt’ or ‘disable’ apoptosis [4Johnstone R.W. et al.Apoptosis: a link between cancer genetics and chemotherapy.Cell. 2002; 108: 153-164Abstract Full Text Full Text PDF PubMed Scopus (2031) Google Scholar, 32Galluzzi L. et al.Mitochondria as therapeutic targets for cancer chemotherapy.Oncogene. 2006; 25: 4812-4830Crossref PubMed Scopus (302) Google Scholar, 33Hanahan D. Weinberg R. The hallmarks of cancer.Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (22805) Google Scholar], which some interpret as meaning that cancer cells are inherently less sensitive to subsequent apoptotic signaling than normal cells. Disruption or disabling of apoptosis would require complete loss of signaling in the mitochondrial apoptotic pathway via, for example, total loss of BAX and BAK expression, yet this is rarely observed in cancers. Cancers commonly upregulate antiapoptotic proteins or downregulate their proapoptotic counterparts to keep apoptosis at bay (reviewed in [30Yip K.W. Reed J.C. Bcl-2 family proteins and cancer.Oncogene. 2008; 27: 6398-6406Crossref PubMed Scopus (728) Google Scholar, 34Juin P. et al.Decoding and unlocking the BCL-2 dependency of cancer cells.Nat. Rev. Cancer. 2013; 13: 455-465Crossref PubMed Scopus (171) Google Scholar]), but this does not equate to disruption or disabling of the apoptotic pathway. In fact, there is little evidence that cancer cells are more refractory to apoptosis than normal cells. Although most cancers have an intact apoptotic pathway, some tumors are even highly primed for apoptosis, as demonstrated by their efficient mitochondrial depolarization in response to proapoptotic signaling in the form of BH3 peptides. This depolarization often exceeds that observed in normal somatic cells [5Ni Chonghaile T. et al.Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy.Science. 2011; 334: 1129-1133Cro
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