A fate worse than death: Apoptosis as an oncogenic process

Nature Reviews Cancer

Volumn 16, Issue 8, 2016, Pages 539-548

  Ichim, Gabriel ^a   Tait, Stephen W G ^a  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

APOPTOSIS; CANCER PREVENTION; CANCER THERAPY; CARCINOGENESIS; CARCINOGENICITY; CELL KILLING; CELL PROLIFERATION; ENDOPLASMIC RETICULUM; HUMAN; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; TUMOR CELL; TUMOR MICROENVIRONMENT; ANIMAL; NEOPLASMS; ONCOGENE; PATHOLOGY; PROGNOSIS;

ANIMALS; APOPTOSIS; CARCINOGENESIS; HUMANS; NEOPLASMS; ONCOGENES; PROGNOSIS;

EID: 84976526702     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc.2016.58     Document Type: Review

References (155)

1. Green, D. R. Means to an End: Apoptosis and Other Cell Death Mechanisms (Cold Spring Harbor Laboratory Press, 2011
2. Mattson, M. P. Apoptosis in neurodegenerative disorders. Nat. Rev. Mol. Cell Biol. 1, 120-129 (2000
3. Nagata, S. Apoptosis and autoimmune diseases. Ann. NY Acad. Sci. 1209, 10-16 (2010
4. Hanahan, D., & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000
5. Delbridge, A. R., Grabow, S., Strasser, A., & Vaux, D. L. Thirty years of BCL 2: translating cell death discoveries into novel cancer therapies. Nat. Rev. Cancer 16, 99-109 (2016
6. Letai, A. G. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat. Rev. Cancer 8, 121-132 (2008
7. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. FDA http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm
8. Roberts, A. W., et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 374, 311-322 (2016
9. Taylor, R. C., Cullen, S. P., & Martin, S. J. Apoptosis: controlled demolition at the cellular level. Nat. Rev. Mol. Cell Biol. 9, 231-241 (2008
10. Czabotar, P. E., Lessene, G., Strasser, A., & Adams, J. M. Control of apoptosis by the BCL 2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 15, 49-63 (2014
11. Tait, S. W., & Green, D. R. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat. Rev. Mol. Cell Biol. 11, 621-632 (2010
12. Li, H., Zhu, H., Xu, C. J., & Yuan, J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491-501 (1998
13. Luo, X., Budihardjo, I., Zou, H., Slaughter, C., & Wang, X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94, 481-490 (1998
14. Tait, S. W., Ichim, G., & Green, D. R. Die another way-non-apoptotic mechanisms of cell death. J. Cell Sci. 127, 2135-2144 (2014
15. Gama, V., et al. The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells. Sci.Signal.7, ra67 (2014
16. Wright, K. M., Linhoff, M. W., Potts, P. R., & Deshmukh, M. Decreased apoptosome activity with neuronal differentiation sets the threshold for strict IAP regulation of apoptosis. J. Cell Biol. 167, 303-313 (2004
17. Colell, A., et al. GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell 129, 983-997 (2007
18. Llambi, F., et al. A unified model of mammalian BCL 2 protein family interactions at the mitochondria. Mol. Cell 44, 517-531 (2011
19. Oltersdorf, T., et al. An inhibitor of Bcl 2 family proteins induces regression of solid tumours. Nature 435, 677-681 (2005
20. Strasser, A., Harris, A. W., Bath, M. L., & Cory, S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl 2. Nature 348, 331-333 (1990
21. Vaux, D. L., Cory, S., & Adams, J. M. Bcl 2 gene promotes haemopoietic cell survival and cooperates with c myc to immortalize pre B cells. Nature 335, 440-442 (1988
22. Finch, A., et al. Bcl xL gain of function and p19 ARF loss of function cooperate oncogenically with Myc in vivo by distinct mechanisms. Cancer Cell 10, 113-120 (2006
23. Yonish-Rouach, E., et al. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin 6. Nature 352, 345-347 (1991
24. Ni Chonghaile, T., et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334, 1129-1133 (2011
25. Montero, J., et al. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell 160, 977-989 (2015
26. Adams, J. M., & Cory, S. The Bcl 2 apoptotic switch in cancer development and therapy. Oncogene 26, 1324-1337 (2007
27. Certo, M., et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL 2 family members. Cancer Cell 9, 351-365 (2006
28. Lopez, J., & Tait, S. W. Mitochondrial apoptosis: killing cancer using the enemy within. Br. J. Cancer 112, 957-962 (2015
29. Wyllie, A. H. The biology of cell death in tumours. Anticancer Res. 5, 131-136 (1985
30. Naresh, K. N., Lakshminarayanan, K., Pai, S. A., & Borges, A. M. Apoptosis index is a predictor of metastatic phenotype in patients with early stage squamous carcinoma of the tongue: a hypothesis to support this paradoxical association. Cancer 91, 578-584 (2001
31. Jalalinadoushan, M., Peivareh, H., & Azizzadeh Delshad, A. Correlation between apoptosis and histological grade of transitional cell carcinoma of urinary bladder. Urol. J. 1, 177-179 (2004
32. Sun, B., et al. Extent, relationship and prognostic significance of apoptosis and cell proliferation in synovial sarcoma. Eur. J. Cancer Prev. 15, 258-265 (2006
33. Alcaide, J., et al. The role and prognostic value of apoptosis in colorectal carcinoma. BMC Clin. Pathol. 13, 24 (2013
34. De Jong, J. S., van Diest, P. J., & Baak, J. P. Number of apoptotic cells as a prognostic marker in invasive breast cancer. Br. J. Cancer 82, 368-373 (2000
35. Dawson, S. J., et al. BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br. J. Cancer 103, 668-675 (2010
36. Anagnostou, V. K., et al. High expression of BCL 2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology. BMC Cancer 10, 186 (2010
37. Renouf, D. J., et al. BCL 2 expression is prognostic for improved survival in non-small cell lung cancer. J. Thorac. Oncol. 4, 486-491 (2009
38. Hogarth, L. A., & Hall, A. G. Increased BAX expression is associated with an increased risk of relapse in childhood acute lymphocytic leukemia. Blood 93, 2671-2678 (1999
39. Kaparou, M., et al. Enhanced levels of the apoptotic BAX/BCL 2 ratio in children with acute lymphoblastic leukemia and high-risk features. Genet. Mol. Biol. 36, 7-11 (2013
40. Del Gaizo Moore, V., et al. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT 737. J. Clin. Invest. 117, 112-121 (2007
41. Ryoo, H. D., Gorenc, T., & Steller, H. Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways. Dev. Cell 7, 491-501 (2004
42. Huh, J. R., Guo, M., & Hay, B. A. Compensatory proliferation induced by cell death in the Drosophila wing disc requires activity of the apical cell death caspase Dronc in a nonapoptotic role. Curr. Biol. 14, 1262-1266 (2004
43. Perez-Garijo, A., Martin, F. A., & Morata, G. Caspase inhibition during apoptosis causes abnormal signalling and developmental aberrations in Drosophila. Development 131, 5591-5598 (2004
44. Li, F., et al. Apoptotic cells activate the phoenix rising pathway to promote wound healing and tissue regeneration. Sci. Signal. 3, ra13 (2010
45. Atsumi, G., et al. Fas-induced arachidonic acid release is mediated by Ca2+-independent phospholipase A2 but not cytosolic phospholipase A2, which undergoes proteolytic inactivation. J. Biol. Chem. 273, 13870-13877 (1998
46. Revesz, L. Effect of tumour cells killed by X rays upon the growth of admixed viable cells. Nature 178, 1391-1392 (1956
47. Chaurio, R., et al. UVB-irradiated apoptotic cells induce accelerated growth of co implanted viable tumor cells in immune competent mice. Autoimmunity 46, 317-322 (2013
48. Huang, Q., et al. Caspase 3 mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17, 860-866 (2011
49. Kurtova, A. V., et al. Blocking PGE2 induced tumour repopulation abrogates bladder cancer chemoresistance. Nature 517, 209-213 (2015
50. Zelenay, S., et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257-1270 (2015
51. Kruiswijk, F., Labuschagne, C. F., & Vousden, K. H. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol. 16, 393-405 (2015
52. Bondar, T., & Medzhitov, R. p53 mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell 6, 309-322 (2010
53. Marusyk, A., Porter, C. C., Zaberezhnyy, V., & DeGregori, J. Irradiation selects for p53 deficient hematopoietic progenitors. PLoS Biol. 8, e1000324 (2010
54. Villunger, A., et al. p53-and drug-induced apoptotic responses mediated by BH3 only proteins Puma and Noxa. Science 302, 1036-1038 (2003
55. Jeffers, J. R., et al. Puma is an essential mediator of p53 dependent and -independent apoptotic pathways. Cancer Cell 4, 321-328 (2003
56. Garrison, S. P., et al. Selection against PUMA gene expression in Myc-driven B cell lymphomagenesis. Mol. Cell. Biol. 28, 5391-5402 (2008
57. Michalak, E. M., et al. Puma and to a lesser extent Noxa are suppressors of Myc-induced lymphomagenesis. Cell Death Differ. 16, 684-696 (2009
58. Michalak, E. M., et al. Apoptosis-promoted tumorigenesis: γ-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death. Genes Dev. 24, 1608-1613 (2010
59. Labi, V., et al. Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation. Genes Dev. 24, 1602-1607 (2010
60. Qiu, W., et al. PUMA-mediated apoptosis drives chemical hepatocarcinogenesis in mice. Hepatology 54, 1249-1258 (2011
61. Pierce, R. H., Vail, M. E., Ralph, L., Campbell, J. S., & Fausto, N. Bcl 2 expression inhibits liver carcinogenesis and delays the development of proliferating foci. Am. J. Pathol. 160, 1555-1560 (2002
62. Orlik, J., et al. The BH3 only protein BID impairs the p38 mediated stress response and promotes hepatocarcinogenesis during chronic liver injury in mice. Hepatology 62, 816-828 (2015
63. Bai, L., Ni, H. M., Chen, X., DiFrancesca, D., & Yin, X. M. Deletion of Bid impedes cell proliferation and hepatic carcinogenesis. Am. J. Pathol. 166, 1523-1532 (2005
64. Bejar, R., & Steensma, D. P. Recent developments in myelodysplastic syndromes. Blood 124, 2793-2803 (2014
65. Ma, X. Epidemiology of myelodysplastic syndromes. Am. J. Med. 125, S2-S5 (2012
66. Godley, L. A., & Larson, R. A. Therapy-related myeloid leukemia. Semin. Oncol. 35, 418-429 (2008
67. Guirguis, A. A., et al. PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia. Cell Death Differ. 23, 1049-1059 (2016
68. Slape, C. I., et al. Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome. Blood 120, 2475-2483 (2012
69. Arandjelovic, S., & Ravichandran, K. S. Phagocytosis of apoptotic cells in homeostasis. Nat. Immunol. 16, 907-917 (2015
70. Tang, J., et al. Upregulation of fractalkine contributes to the proliferative response of prostate cancer cells to hypoxia via promoting the G1/S phase transition. Mol. Med. Rep. 12, 7907-7914 (2015
71. Tardaguila, M., & Manes, S. CX3CL1 at the crossroad of EGF signals: relevance for the progression of ERBB2 breast carcinoma. Oncoimmunology 2, e25669 (2013
72. Elliott, M. R., et al. Nucleotides released by apoptotic cells act as a find me signal to promote phagocytic clearance. Nature 461, 282-286 (2009
73. Spychala, J. Tumor-promoting functions of adenosine. Pharmacol. Ther. 87, 161-173 (2000
74. Gregory, C. D., & Pound, J. D. Cell death in the neighbourhood: direct microenvironmental effects of apoptosis in normal and neoplastic tissues. J. Pathol. 223, 177-194 (2011
75. Noy, R., & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49-61 (2014
76. Ford, C. A., et al. Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma. Curr. Biol. 25, 577-588 (2015
77. Stanford, J. C., et al. Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J. Clin. Invest. 124, 4737-4752 (2014
78. Callihan, E. B., et al. Postpartum diagnosis demonstrates a high risk for metastasis and merits an expanded definition of pregnancy-associated breast cancer. Breast Cancer Res. Treat. 138, 549-559 (2013
79. Schedin, P. J., & Watson, C. J. The complexity of the relationships between age at first birth and breast cancer incidence curves implicate pregnancy in cancer initiation as well as promotion of existing lesions. J. Mammary Gland Biol. Neoplasia 14, 85-86 (2009
80. Ichim, G., et al. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol. Cell 57, 860-872 (2015
81. Lovric, M. M., & Hawkins, C. J. TRAIL treatment provokes mutations in surviving cells. Oncogene 29, 5048-5060 (2010
82. Liu, X., et al. Caspase 3 promotes genetic instability and carcinogenesis. Mol. Cell 58, 284-296 (2015
83. Goldstein, J. C., Waterhouse, N. J., Juin, P., Evan, G. I., & Green, D. R. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat. Cell Biol. 2, 156-162 (2000
84. Rehm, M., Dussmann, H., & Prehn, J. H. Real-time single cell analysis of Smac/DIABLO release during apoptosis. J. Cell Biol. 162, 1031-1043 (2003
85. Rehm, M., Huber, H. J., Dussmann, H., & Prehn, J. H. Systems analysis of effector caspase activation and its control by X linked inhibitor of apoptosis protein. EMBO J. 25, 4338-4349 (2006
86. Walczak, H., et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat. Med. 5, 157-163 (1999
87. Albeck, J. G., et al. Quantitative analysis of pathways controlling extrinsic apoptosis in single cells. Mol. Cell 30, 11-25 (2008
88. Enari, M., et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391, 43-50 (1998
89. Galluzzi, L., Larochette, N., Zamzami, N., & Kroemer, G. Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene 25, 4812-4830 (2006
90. Tait, S. W., et al. Resistance to caspase-independent cell death requires persistence of intact mitochondria. Dev. Cell 18, 802-813 (2010
91. Orth, J. D., Loewer, A., Lahav, G., & Mitchison, T. J. Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction. Mol. Biol. Cell 23, 567-576 (2012
92. Colin, D. J., Hain, K. O., Allan, L. A., & Clarke, P. R. Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl 2 family proteins. Open Biol. 5, 140156 (2015
93. Luke, J. J., Van De Wetering, C. I., & Knudson, C. M. Lymphoma development in Bax transgenic mice is inhibited by Bcl 2 and associated with chromosomal instability. Cell Death Differ. 10, 740-748 (2003
94. Rao, R. C., & Dou, Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat. Rev. Cancer 15, 334-346 (2015
95. Gole, B., & Wiesmuller, L. Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)-multiple rather than a single mechanism. Front. Cell Dev. Biol. 3, 41 (2015
96. Hars, E. S., Lyu, Y. L., Lin, C. P., & Liu, L. F. Role of apoptotic nuclease caspase-activated DNase in etoposide-induced treatment-related acute myelogenous leukemia. Cancer Res. 66, 8975-8979 (2006
97. Sim, S. P., & Liu, L. F. Nucleolytic cleavage of the mixed lineage leukemia breakpoint cluster region during apoptosis. J. Biol. Chem. 276, 31590-31595 (2001
98. Betti, C. J., Villalobos, M. J., Diaz, M. O., & Vaughan, A. T. Apoptotic stimuli initiate MLL-AF9 translocations that are transcribed in cells capable of division. Cancer Res. 63, 1377-1381 (2003
99. Trinchieri, G. Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu. Rev. Immunol. 30, 677-706 (2012
100. Fresquet, V., Rieger, M., Carolis, C., Garcia Barchino, M. J., & Martinez-Climent, J. A. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT 199 in lymphoma. Blood 123, 4111-4119 (2014
101. Song, J. H., Kandasamy, K., Zemskova, M., Lin, Y. W., & Kraft, A. S. The BH3 mimetic ABT 737 induces cancer cell senescence. Cancer Res. 71, 506-515 (2011
102. Fuchs, Y., & Steller, H. Programmed cell death in animal development and disease. Cell 147, 742-758 (2011
103. Hardwick, J. M., & Soane, L. Multiple functions of BCL 2 family proteins. Cold Spring Harb. Perspect. Biol. 5, a008722 (2013
104. Hyman, B. T., & Yuan, J. Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology. Nat. Rev. Neurosci. 13, 395-406 (2012
105. Kilbride, S. M., & Prehn, J. H. Central roles of apoptotic proteins in mitochondrial function. Oncogene 32, 2703-2711 (2013
106. Bonneau, B., Prudent, J., Popgeorgiev, N., & Gillet, G. Non-apoptotic roles of Bcl 2 family: the calcium connection. Biochim. Biophys. Acta 1833, 1755-1765 (2013
107. Pedro, J. M., et al. BAX and BAK1 are dispensable for ABT 737 induced dissociation of the BCL2-BECN1 complex and autophagy. Autophagy 11, 452-459 (2015
108. Lindqvist, L. M., Heinlein, M., Huang, D. C., & Vaux, D. L. Prosurvival Bcl 2 family members affect autophagy only indirectly, by inhibiting Bax and Bak. Proc. Natl Acad. Sci. USA 111, 8512-8517 (2014
109. Choi, S., et al. Bcl xL promotes metastasis independent of its anti-apoptotic activity. Nat. Commun. 7, 10384 (2016
110. Dimberg, L. Y., et al. On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics. Oncogene 32, 1341-1350 (2013
111. Von Karstedt, S., et al. Cancer cell-autonomous TRAIL R signaling promotes KRAS-driven cancer progression, invasion, and metastasis. Cancer Cell 27, 561-573 (2015
112. Somasekharan, S. P., et al. TRAIL promotes membrane blebbing, detachment and migration of cells displaying a dysfunctional intrinsic pathway of apoptosis. Apoptosis 18, 324-336 (2013
113. Ehrenschwender, M., et al. Mutant PIK3CA licenses TRAIL and CD95L to induce non-apoptotic caspase 8 mediated ROCK activation. Cell Death Differ. 17, 1435-1447 (2010
114. Peter, M. E., et al. The role of CD95 and CD95 ligand in cancer. Cell Death Differ. 22, 885-886 (2015
115. Chen, L., et al. CD95 promotes tumour growth. Nature 465, 492-496 (2010
116. Hadji, A., et al. Death induced by CD95 or CD95 ligand elimination. Cell Rep. 7, 208-222 (2014
117. Ceppi, P., et al. CD95 and CD95L promote and protect cancer stem cells. Nat. Commun. 5, 5238 (2014
118. Fanidi, A., Harrington, E. A., & Evan, G. I. Cooperative interaction between c myc and bcl 2 proto-oncogenes. Nature 359, 554-556 (1992
119. Schmitt, C. A., Rosenthal, C. T., & Lowe, S. W. Genetic analysis of chemoresistance in primary murine lymphomas. Nat. Med. 6, 1029-1035 (2000
120. Letai, A., Sorcinelli, M. D., Beard, C., & Korsmeyer, S. J. Antiapoptotic BCL 2 is required for maintenance of a model leukemia. Cancer Cell 6, 241-249 (2004
121. Kelly, G. L., et al. Targeting of MCL 1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53. Genes Dev. 28, 58-70 (2014
122. Garcia, E. L., & Mills, A. A. Getting around lethality with inducible Cre-mediated excision. Semin. Cell Dev. Biol. 13, 151-158 (2002
123. Lopez, J., et al. Mito-priming as a method to engineer Bcl 2 addiction. Nat. Commun. 7, 10538 (2016
124. Zhang, J., et al. Visualization of caspase 3 like activity in cells using a genetically encoded fluorescent biosensor activated by protein cleavage. Nat. Commun. 4, 2157 (2013
125. Earley, S., et al. In vivo imaging of drug-induced mitochondrial outer membrane permeabilization at single-cell resolution. Cancer Res. 72, 2949-2956 (2012
126. Ellenbroek, S. I., & van Rheenen, J. Imaging hallmarks of cancer in living mice. Nat. Rev. Cancer 14, 406-418 (2014
127. Janssen, A., Beerling, E., Medema, R., & van Rheenen, J. Intravital FRET imaging of tumor cell viability and mitosis during chemotherapy. PLoS ONE 8, e64029 (2013
128. Kim, K. W., Moretti, L., & Lu, B. M867, a novel selective inhibitor of caspase 3 enhances cell death and extends tumor growth delay in irradiated lung cancer models. PLoS ONE 3, e2275 (2008
129. Werthmoller, N., Frey, B., Wunderlich, R., Fietkau, R., & Gaipl, U. S. Modulation of radiochemoimmunotherapy-induced B16 melanoma cell death by the pan-caspase inhibitor zVAD-fmk induces anti-tumor immunity in a HMGB1-, nucleotide-and T cell-dependent manner. Cell Death Dis. 6, e1761 (2015
130. Rongvaux, A., et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563-1577 (2014
131. White, M. J., et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159, 1549-1562 (2014
132. Ahn, J., et al. Inflammation-driven carcinogenesis is mediated through STING. Nat. Commun. 5, 5166 (2014
133. Ahn, J., Konno, H., & Barber, G. N. Diverse roles of STING-dependent signaling on the development of cancer. Oncogene 34, 5302-5308 (2015
134. Xiang, J., Chao, D. T., & Korsmeyer, S. J. BAX-induced cell death may not require interleukin 1β-converting enzyme-like proteases. Proc. Natl Acad. Sci. USA 93, 14559-14563 (1996
135. Schreiber, R. D., Old, L. J., & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565-1570 (2011
136. Swann, J. B., & Smyth, M. J. Immune surveillance of tumors. J. Clin. Invest. 117, 1137-1146 (2007
137. Pyonteck, S. M., et al. CSF 1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264-1272 (2013
138. Ries, C. H., et al. Targeting tumor-associated macrophages with anti-CSF 1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846-859 (2014
139. Fulda, S., & Vucic, D. Targeting IAP proteins for therapeutic intervention in cancer. Nat. Rev. Drug Discov. 11, 109-124 (2012
140. Tait, S. W., & Green, D. R. Mitochondrial regulation of cell death. Cold Spring Harb. Perspect. Biol. 5, a008706 (2013
141. Hellwig, C. T., et al. Real time analysis of tumor necrosis factor-related apoptosis-inducing ligand/cycloheximide-induced caspase activities during apoptosis initiation. J. Biol. Chem. 283, 21676-21685 (2008
142. Hellwig, C. T., et al. Activity of protein kinase CK2 uncouples Bid cleavage from caspase 8 activation. J. Cell Sci. 123, 1401-1406 (2010
143. Desagher, S., et al. Phosphorylation of bid by casein kinases I and II regulates its cleavage by caspase 8. Mol. Cell 8, 601-611 (2001
144. Wolan, D. W., Zorn, J. A., Gray, D. C., & Wells, J. A. Small-molecule activators of a proenzyme. Science 326, 853-858 (2009
145. Vakkila, J., & Lotze, M. T. Inflammation and necrosis promote tumour growth. Nat. Rev. Immunol. 4, 641-648 (2004
146. Grivennikov, S. I., Greten, F. R., & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883-899 (2010
147. Berardo, M. D., et al. bcl 2 and apoptosis in lymph node positive breast carcinoma. Cancer 82, 1296-1302 (1998
148. Vargas-Roig, L. M., et al. Prognostic value of Bcl 2 in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy. Mol. Oncol. 2, 102-111 (2008
149. Neri, A.et al. Bcl-2 expression correlates with lymphovascular invasion and long-term prognosis in breast cancer. Breast Cancer Res. Treat. 99, 77-83 (2006
150. Meterissian, S. H., et al. Bcl 2 is a useful prognostic marker in Dukes' B colon cancer. Ann. Surg. Oncol. 8, 533-537 (2001
151. Watson, N. F., et al. Evidence that the p53 negative/Bcl 2 positive phenotype is an independent indicator of good prognosis in colorectal cancer: a tissue microarray study of 460 patients. World J. Surg. Oncol. 3, 47 (2005
152. Tomita, M., et al. Prognostic significance of bcl 2 expression in resected pN2 non-small cell lung cancer. Eur. J. Surg. Oncol. 29, 654-657 (2003
153. Pillai, K., Pourgholami, M. H., Chua, T. C., & Morris, D. L. Does the expression of BCL2 have prognostic significance in malignant peritoneal mesothelioma? Am. J. Cancer Res. 3, 312-322 (2013
154. Kohler, T., et al. High Bad and Bax mRNA expression correlate with negative outcome in acute myeloid leukemia (AML). Leukemia 16, 22-29 (2002
155. Bairey, O., Zimra, Y., Shaklai, M., Okon, E., & Rabizadeh, E. Bcl 2, Bcl X, Bax, and Bak expression in short-and long-lived patients with diffuse large B cell lymphomas. Clin. Cancer Res. 5, 2860-2866 (1999