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Open Access 01-12-2014 | Review

Putting the pieces together: How is the mitochondrial pathway of apoptosis regulated in cancer and chemotherapy?

Authors: Rana Elkholi, Thibaud T Renault, Madhavika N Serasinghe, Jerry E Chipuk

Published in: Cancer & Metabolism | Issue 1/2014

Abstract

In order to solve a jigsaw puzzle, one must first have the complete picture to logically connect the pieces. However, in cancer biology, we are still gaining an understanding of all the signaling pathways that promote tumorigenesis and how these pathways can be pharmacologically manipulated by conventional and targeted therapies. Despite not having complete knowledge of the mechanisms that cause cancer, the signaling networks responsible for cancer are becoming clearer, and this information is serving as a solid foundation for the development of rationally designed therapies. One goal of chemotherapy is to induce cancer cell death through the mitochondrial pathway of apoptosis. Within this review, we present the pathways that govern the cellular decision to undergo apoptosis as three distinct, yet connected puzzle pieces: (1) How do oncogene and tumor suppressor pathways regulate apoptosis upstream of mitochondria? (2) How does the B-cell lymphoma 2 (BCL-2) family influence tumorigenesis and chemotherapeutic responses? (3) How is post-mitochondrial outer membrane permeabilization (MOMP) regulation of cell death relevant in cancer? When these pieces are united, it is possible to appreciate how cancer signaling directly impacts upon the fundamental cellular mechanisms of apoptosis and potentially reveals novel pharmacological targets within these pathways that may enhance chemotherapeutic success.

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Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR: The BCL-2 family reunion. Mol Cell. 2010, 37 (3): 299-310. 10.1016/j.molcel.2010.01.025.PubMedPubMedCentral

Tait SW, Green DR: Mitochondrial regulation of cell death. Cold Spring Harb Perspect Biol. 2013, 5 (9):

Walensky LD, Gavathiotis E: BAX unleashed: the biochemical transformation of an inactive cytosolic monomer into a toxic mitochondrial pore. Trends Biochem Sci. 2011, 36 (12): 642-652. 10.1016/j.tibs.2011.08.009.PubMedPubMedCentral

Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell. 2011, 144 (5): 646-674. 10.1016/j.cell.2011.02.013.PubMed

Delbridge AR, Valente LJ, Strasser A: The role of the apoptotic machinery in tumor suppression. Cold Spring Harb Perspect Biol. 2012, 4 (11):

Shortt J, Johnstone RW: Oncogenes in cell survival and cell death. Cold Spring Harb Perspect Biol. 2012, 4 (12):

Vousden KH, Prives C: Blinded by the light: the growing complexity of p53. Cell. 2009, 137 (3): 413-431. 10.1016/j.cell.2009.04.037.PubMed

Vousden KH, Lane DP: p53 in health and disease. Nat Rev Mol Cell Biol. 2007, 8 (4): 275-283. 10.1038/nrm2147.PubMed

Vogelstein B, Lane D, Levine AJ: Surfing the p53 network. Nature. 2000, 408 (6810): 307-310. 10.1038/35042675.PubMed

10.

Sengupta S, Harris CC: p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol. 2005, 6 (1): 44-55. 10.1038/nrm1546.PubMed

11.

Mirza A, Wu Q, Wang L, McClanahan T, Bishop WR, Gheyas F, Ding W, Hutchins B, Hockenberry T, Kirschmeier P, Greene JR, Liu S: Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression. Oncogene. 2003, 22 (23): 3645-3654. 10.1038/sj.onc.1206477.PubMed

12.

Miyashita T, Reed JC: Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995, 80 (2): 293-299. 10.1016/0092-8674(95)90412-3.PubMed

13.

Nakano K, Vousden KH: PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 2001, 7 (3): 683-694. 10.1016/S1097-2765(01)00214-3.PubMed

14.

Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N: Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 2000, 288 (5468): 1053-1058. 10.1126/science.288.5468.1053.PubMed

15.

Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B: PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell. 2001, 7 (3): 673-682. 10.1016/S1097-2765(01)00213-1.PubMed

16.

Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR: Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 2004, 303 (5660): 1010-1014. 10.1126/science.1092734.PubMed

17.

Leu JI, Dumont P, Hafey M, Murphy ME, George DL: Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol. 2004, 6 (5): 443-450. 10.1038/ncb1123.PubMed

18.

Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM: p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003, 11 (3): 577-590. 10.1016/S1097-2765(03)00050-9.PubMed

19.

Mihara M, Moll UM: Detection of mitochondrial localization of p53. Methods Mol Biol. 2003, 234: 203-209.PubMed

20.

Kitamura H, Yazawa T, Sato H, Okudela K, Shimoyamada H: Small cell lung cancer: significance of RB alterations and TTF-1 expression in its carcinogenesis, phenotype, and biology. Endocr Pathol. 2009, 20 (2): 101-107. 10.1007/s12022-009-9072-4.PubMed

21.

Lee WH, Shew JY, Hong FD, Sery TW, Donoso LA, Young LJ, Bookstein R, Lee EY: The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity. Nature. 1987, 329 (6140): 642-645. 10.1038/329642a0.PubMed

22.

Miller CW, Aslo A, Won A, Tan M, Lampkin B, Koeffler HP: Alterations of the p53, Rb and MDM2 genes in osteosarcoma. J Cancer Res Clin Oncol. 1996, 122 (9): 559-565. 10.1007/BF01213553.PubMed

23.

Wang NP, To H, Lee WH, Lee EY: Tumor suppressor activity of RB and p53 genes in human breast carcinoma cells. Oncogene. 1993, 8 (2): 279-288.PubMed

24.

Knudsen ES, Wang JY: Targeting the RB-pathway in cancer therapy. Clin Cancer Res. 2010, 16 (4): 1094-1099. 10.1158/1078-0432.CCR-09-0787.PubMedPubMedCentral

25.

Harbour JW, Dean DC: The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 2000, 14 (19): 2393-2409. 10.1101/gad.813200.PubMed

26.

Araki K, Kawauchi K, Tanaka N: IKK/NF-kappaB signaling pathway inhibits cell-cycle progression by a novel Rb-independent suppression system for E2F transcription factors. Oncogene. 2008, 27 (43): 5696-5705. 10.1038/onc.2008.184.PubMed

27.

Bowen C, Spiegel S, Gelmann EP: Radiation-induced apoptosis mediated by retinoblastoma protein. Cancer Res. 1998, 58 (15): 3275-3281.PubMed

28.

Bowen C, Birrer M, Gelmann EP: Retinoblastoma protein-mediated apoptosis after gamma-irradiation. J Biol Chem. 2002, 277 (47): 44969-44979. 10.1074/jbc.M202000200.PubMed

29.

Knudsen KE, Weber E, Arden KC, Cavenee WK, Feramisco JR, Knudsen ES: The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death. Oncogene. 1999, 18 (37): 5239-5245. 10.1038/sj.onc.1202910.PubMed

30.

Almasan A, Yin Y, Kelly RE, Lee EY, Bradley A, Li W, Bertino JR, Wahl GM: Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. Proc Natl Acad Sci U S A. 1995, 92 (12): 5436-5440. 10.1073/pnas.92.12.5436.PubMedPubMedCentral

31.

Bosco EE, Mayhew CN, Hennigan RF, Sage J, Jacks T, Knudsen ES: RB signaling prevents replication-dependent DNA double-strand breaks following genotoxic insult. Nucleic Acids Res. 2004, 32 (1): 25-34. 10.1093/nar/gkg919.PubMedPubMedCentral

32.

Knudsen KE, Booth D, Naderi S, Sever-Chroneos Z, Fribourg AF, Hunton IC, Feramisco JR, Wang JY, Knudsen ES: RB-dependent S-phase response to DNA damage. Mol Cell Biol. 2000, 20 (20): 7751-7763. 10.1128/MCB.20.20.7751-7763.2000.PubMedPubMedCentral

33.

Ianari A, Natale T, Calo E, Ferretti E, Alesse E, Screpanti I, Haigis K, Gulino A, Lees JA: Proapoptotic function of the retinoblastoma tumor suppressor protein. Cancer Cell. 2009, 15 (3): 184-194. 10.1016/j.ccr.2009.01.026.PubMedPubMedCentral

34.

Ferecatu I, Le Floch N, Bergeaud M, Rodriguez-Enfedaque A, Rincheval V, Oliver L, Vallette FM, Mignotte B, Vayssiere JL: Evidence for a mitochondrial localization of the retinoblastoma protein. BMC Cell Biol. 2009, 10: 50-10.1186/1471-2121-10-50.PubMedPubMedCentral

35.

Hilgendorf KI, Leshchiner ES, Nedelcu S, Maynard MA, Calo E, Ianari A, Walensky LD, Lees JA: The retinoblastoma protein induces apoptosis directly at the mitochondria. Genes Dev. 2013, 27 (9): 1003-1015. 10.1101/gad.211326.112.PubMedPubMedCentral

36.

Macleod KF, Hu Y, Jacks T: Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. EMBO J. 1996, 15 (22): 6178-6188.PubMedPubMedCentral

37.

Morgenbesser SD, Williams BO, Jacks T, DePinho RA: p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature. 1994, 371 (6492): 72-74. 10.1038/371072a0.PubMed

38.

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013, 6 (269): l1-

39.

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N: The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012, 2 (5): 401-404. 10.1158/2159-8290.CD-12-0095.PubMed

40.

Leslie NR, Brunton VG: Cell biology. Where is PTEN?. Science. 2013, 341 (6144): 355-356. 10.1126/science.1242541.PubMed

41.

Hopkins BD, Hodakoski C, Barrows D, Mense SM, Parsons RE: PTEN function: the long and the short of it. Trends Biochem Sci. 2014, 39 (4): 183-190. 10.1016/j.tibs.2014.02.006.PubMedPubMedCentral

42.

Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW: Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998, 95 (1): 29-39. 10.1016/S0092-8674(00)81780-8.PubMed

43.

Datta SR, Brunet A, Greenberg ME: Cellular survival: a play in three Akts. Genes Dev. 1999, 13 (22): 2905-2927. 10.1101/gad.13.22.2905.PubMed

44.

Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ: Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol. 2000, 10 (19): 1201-1204. 10.1016/S0960-9822(00)00728-4.PubMed

45.

Dudgeon C, Wang P, Sun X, Peng R, Sun Q, Yu J, Zhang L: PUMA induction by FoxO3a mediates the anticancer activities of the broad-range kinase inhibitor UCN-01. Mol Cancer Ther. 2010, 9 (11): 2893-2902. 10.1158/1535-7163.MCT-10-0635.PubMedPubMedCentral

46.

Dan HC, Sun M, Kaneko S, Feldman RI, Nicosia SV, Wang HG, Tsang BK, Cheng JQ: Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem. 2004, 279 (7): 5405-5412. 10.1074/jbc.M312044200.PubMed

47.

Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997, 91 (2): 231-241. 10.1016/S0092-8674(00)80405-5.PubMed

48.

del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G: Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science. 1997, 278 (5338): 687-689. 10.1126/science.278.5338.687.PubMed

49.

Capon DJ, Seeburg PH, McGrath JP, Hayflick JS, Edman U, Levinson AD, Goeddel DV: Activation of Ki-ras2 gene in human colon and lung carcinomas by two different point mutations. Nature. 1983, 304 (5926): 507-513. 10.1038/304507a0.PubMed

50.

Chang EH, Furth ME, Scolnick EM, Lowy DR: Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus. Nature. 1982, 297 (5866): 479-483. 10.1038/297479a0.PubMed

51.

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J: Mutations of the BRAF gene in human cancer. Nature. 2002, 417 (6892): 949-954. 10.1038/nature00766.PubMed

52.

Downward J: Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003, 3 (1): 11-22. 10.1038/nrc969.PubMed

53.

Pratilas CA, Solit DB: Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response. Clin Cancer Res. 2010, 16 (13): 3329-3334. 10.1158/1078-0432.CCR-09-3064.PubMedPubMedCentral

54.

Kinoshita T, Yokota T, Arai K, Miyajima A: Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells. Oncogene. 1995, 10 (11): 2207-2212.PubMed

55.

Domina AM, Vrana JA, Gregory MA, Hann SR, Craig RW: MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene. 2004, 23 (31): 5301-5315. 10.1038/sj.onc.1207692.PubMed

56.

Biswas SC, Greene LA: Nerve growth factor (NGF) down-regulates the Bcl-2 homology 3 (BH3) domain-only protein Bim and suppresses its proapoptotic activity by phosphorylation. J Biol Chem. 2002, 277 (51): 49511-49516. 10.1074/jbc.M208086200.PubMed

57.

Goldstein NB, Johannes WU, Gadeliya AV, Green MR, Fujita M, Norris DA, Shellman YG: Active N-Ras and B-Raf inhibit anoikis by downregulating Bim expression in melanocytic cells. J Invest Dermatol. 2009, 129 (2): 432-437. 10.1038/jid.2008.227.PubMed

58.

Hubner A, Barrett T, Flavell RA, Davis RJ: Multisite phosphorylation regulates Bim stability and apoptotic activity. Mol Cell. 2008, 30 (4): 415-425. 10.1016/j.molcel.2008.03.025.PubMedPubMedCentral

59.

Jiang CC, Lai F, Tay KH, Croft A, Rizos H, Becker TM, Yang F, Liu H, Thorne RF, Hersey P, Zhang XD: Apoptosis of human melanoma cells induced by inhibition of B-RAFV600E involves preferential splicing of bimS. Cell Death Dis. 2010, 1: e69-10.1038/cddis.2010.48.PubMedPubMedCentral

60.

Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen YA, Munko AC, Wood E, Fedorenko IV, Sondak VK, Anderson AR, Ribas A, Palma MD, Nathanson KL, Koomen JM, Messina JL, Smalley KS: PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011, 71 (7): 2750-2760. 10.1158/0008-5472.CAN-10-2954.PubMedPubMedCentral

61.

Serasinghe MN, Missert DJ, Asciolla JJ, Podgrabinska S, Wieder SY, Izadmehr S, Belbin G, Skobe M, Chipuk JE: Anti-apoptotic BCL-2 proteins govern cellular outcome following B-RAF inhibition and can be targeted to reduce resistance. Oncogene. 2014, 0: doi:10.1038/onc.2014.21

62.

Joseph EW, Pratilas CA, Poulikakos PI, Tadi M, Wang W, Taylor BS, Halilovic E, Persaud Y, Xing F, Viale A, Tsai J, Chapman PB, Bollag G, Solit DB, Rosen N: The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A. 2010, 107 (33): 14903-14908. 10.1073/pnas.1008990107.PubMedPubMedCentral

63.

Allan LA, Morrice N, Brady S, Magee G, Pathak S, Clarke PR: Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol. 2003, 5 (7): 647-654. 10.1038/ncb1005.PubMed

64.

Fang X, Yu S, Eder A, Mao M, Bast RC, Boyd D, Mills GB: Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene. 1999, 18 (48): 6635-6640. 10.1038/sj.onc.1203076.PubMed

65.

Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ: p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci U S A. 2001, 98 (17): 9666-9670. 10.1073/pnas.171301998.PubMedPubMedCentral

66.

Kim J, Parrish AB, Kurokawa M, Matsuura K, Freel CD, Andersen JL, Johnson CE, Kornbluth S: Rsk-mediated phosphorylation and 14-3-3varepsilon binding of Apaf-1 suppresses cytochrome c-induced apoptosis. EMBO J. 2012, 31 (5): 1279-1292. 10.1038/emboj.2011.491.PubMedPubMedCentral

67.

Nilsson JA, Cleveland JL: Myc pathways provoking cell suicide and cancer. Oncogene. 2003, 22 (56): 9007-9021. 10.1038/sj.onc.1207261.PubMed

68.

Green DR, Evan GI: A matter of life and death. Cancer Cell. 2002, 1 (1): 19-30. 10.1016/S1535-6108(02)00024-7.PubMed

69.

Hemann MT, Bric A, Teruya-Feldstein J, Herbst A, Nilsson JA, Cordon-Cardo C, Cleveland JL, Tansey WP, Lowe SW: Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature. 2005, 436 (7052): 807-811. 10.1038/nature03845.PubMedPubMedCentral

70.

Terunuma A, Putluri N, Mishra P, Mathe EA, Dorsey TH, Yi M, Wallace TA, Issaq HJ, Zhou M, Killian JK, Stevenson HS, Karoly ED, Chan K, Samanta S, Prieto D, Hsu TY, Kurley SJ, Putluri V, Sonavane R, Edelman DC, Wulff J, Starks AM, Yang Y, Kittles RA, Yfantis HG, Lee DH, Ioffe OB, Schiff R, Stephens RM, Meltzer PS, Veenstra TD, Westbrook TF, Sreekumar A, Ambs S: MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest. 2014, 124 (1): 398-412. 10.1172/JCI71180.PubMedPubMedCentral

71.

Tsujimoto Y, Gorham J, Cossman J, Jaffe E, Croce CM: The T(14,18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science. 1985, 229 (4720): 1390-1392. 10.1126/science.3929382.PubMed

72.

Vaux DL: Immunopathology of apoptosis—introduction and overview. Springer Semin Immunopathol. 1998, 19 (3): 271-278. 10.1007/BF00787224.PubMed

73.

Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, Archimbaud E, Magaud JP, Guyotat D: High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood. 1993, 81 (11): 3091-3096.PubMed

74.

Frommel TO, Yong S, Zarling EJ: Immunohistochemical evaluation of Bcl-2 gene family expression in liver of hepatitis C and cirrhotic patients: a novel mechanism to explain the high incidence of hepatocarcinoma in cirrhotics. Am J Gastroenterol. 1999, 94 (1): 178-182. 10.1111/j.1572-0241.1999.00792.x.PubMed

75.

Lai C, Grant C, Dunleavy K: Interpreting MYC and BCL2 in diffuse large B-cell lymphoma. Leuk Lymphoma. 2013, 54 (10): 2091-2092. 10.3109/10428194.2013.806803.PubMed

76.

Steinert DM, Oyarzo M, Wang X, Choi H, Thall PF, Medeiros LJ, Raymond AK, Benjamin RS, Zhang W, Trent JC: Expression of Bcl-2 in gastrointestinal stromal tumors: correlation with progression-free survival in 81 patients treated with imatinib mesylate. Cancer. 2006, 106 (7): 1617-1623. 10.1002/cncr.21781.PubMed

77.

Renault TT, Chipuk JE: Death upon a kiss: mitochondrial outer membrane composition and organelle communication govern sensitivity to BAK/BAX-dependent apoptosis. Chem Biol. 2014, 21 (1): 114-123. 10.1016/j.chembiol.2013.10.009.PubMedPubMedCentral

78.

Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD: Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell. 2002, 111 (3): 331-342. 10.1016/S0092-8674(02)01036-X.PubMed

79.

Chipuk JE, McStay GP, Bharti A, Kuwana T, Clarke CJ, Siskind LJ, Obeid LM, Green DR: Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell. 2012, 148 (5): 988-1000. 10.1016/j.cell.2012.01.038.PubMedPubMedCentral

80.

Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD: BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell. 2005, 17 (4): 525-535. 10.1016/j.molcel.2005.02.003.PubMed

81.

Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ: Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002, 2 (3): 183-192. 10.1016/S1535-6108(02)00127-7.PubMed

82.

Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD: BAX activation is initiated at a novel interaction site. Nature. 2008, 455 (7216): 1076-1081. 10.1038/nature07396.PubMedPubMedCentral

83.

Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou JC: Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol. 1999, 144 (5): 891-901. 10.1083/jcb.144.5.891.PubMedPubMedCentral

84.

Czabotar PE, Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD, Lee EF, Yao S, Robin AY, Smith BJ, Huang DC, Kluck RM, Adams JM, Colman PM: Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell. 2013, 152 (3): 519-531. 10.1016/j.cell.2012.12.031.PubMed

85.

Chipuk JE, Fisher JC, Dillon CP, Kriwacki RW, Kuwana T, Green DR: Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins. Proc Natl Acad Sci U S A. 2008, 105 (51): 20327-20332. 10.1073/pnas.0808036105.PubMedPubMedCentral

86.

Renault TT, Chipuk JE: Getting away with murder: how does the BCL-2 family of proteins kill with immunity?. Ann N Y Acad Sci. 2013, 1285: 59-79. 10.1111/nyas.12045.PubMedPubMedCentral

87.

Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC: bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood. 1993, 82 (6): 1820-1828.PubMed

88.

Certo M, Del Gaizo MV, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A: Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 2006, 9 (5): 351-365. 10.1016/j.ccr.2006.03.027.PubMed

89.

Ni Chonghaile T, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore Vdel G, Deng J, Anderson KC, Richardson P, Tai YT, Mitsiades CS, Matulonis UA, Drapkin R, Stone R, Deangelo DJ, McConkey DJ, Sallan SE, Silverman L, Hirsch MS, Carrasco DR, Letai A: Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science. 2011, 334 (6059): 1129-1133. 10.1126/science.1206727.PubMed

90.

Ryan JA, Brunelle JK, Letai A: Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes. Proc Natl Acad Sci U S A. 2010, 107 (29): 12895-12900. 10.1073/pnas.0914878107.PubMedPubMedCentral

91.

Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM: miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005, 102 (39): 13944-13949. 10.1073/pnas.0506654102.PubMedPubMedCentral

92.

Zhu DX, Zhu W, Fang C, Fan L, Zou ZJ, Wang YH, Liu P, Hong M, Miao KR, Liu P, Xu W, Li JY: miR-181a/b significantly enhances drug sensitivity in chronic lymphocytic leukemia cells via targeting multiple anti-apoptosis genes. Carcinogenesis. 2012, 33 (7): 1294-1301. 10.1093/carcin/bgs179.PubMed

93.

She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J, Rosen N: The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell. 2005, 8 (4): 287-297. 10.1016/j.ccr.2005.09.006.PubMedPubMedCentral

94.

Paterson A, Mockridge CI, Adams JE, Krysov S, Potter KN, Duncombe AS, Cook SJ, Stevenson FK, Packham G: Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia. Blood. 2012, 119 (7): 1726-1736. 10.1182/blood-2011-07-367417.PubMed

95.

Kitada S, Leone M, Sareth S, Zhai D, Reed JC, Pellecchia M: Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J Med Chem. 2003, 46 (20): 4259-4264. 10.1021/jm030190z.PubMed

96.

Mohammad RM, Goustin AS, Aboukameel A, Chen B, Banerjee S, Wang G, Nikolovska-Coleska Z, Wang S, Al-Katib A: Preclinical studies of TW-37, a new nonpeptidic small-molecule inhibitor of Bcl-2, in diffuse large cell lymphoma xenograft model reveal drug action on both Bcl-2 and Mcl-1. Clin Cancer Res. 2007, 13 (7): 2226-2235. 10.1158/1078-0432.CCR-06-1574.PubMed

97.

Wang G, Nikolovska-Coleska Z, Yang CY, Wang R, Tang G, Guo J, Shangary S, Qiu S, Gao W, Yang D, Meagher J, Stuckey J, Krajewski K, Jiang S, Roller PP, Abaan HO, Tomita Y, Wang S: Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J Med Chem. 2006, 49 (21): 6139-6142. 10.1021/jm060460o.PubMed

98.

Wei J, Kitada S, Stebbins JL, Placzek W, Zhai D, Wu B, Rega MF, Zhang Z, Cellitti J, Yang L, Dahl R, Reed JC, Pellecchia M: Synthesis and biological evaluation of Apogossypolone derivatives as pan-active inhibitors of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins. J Med Chem. 2010, 53 (22): 8000-8011. 10.1021/jm100746q.PubMedPubMedCentral

99.

Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH: An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005, 435 (7042): 677-681. 10.1038/nature03579.PubMed

100.

Mason EF, Rathmell JC: Cell metabolism: an essential link between cell growth and apoptosis. Biochim Biophys Acta. 2011, 1813 (4): 645-654. 10.1016/j.bbamcr.2010.08.011.PubMedPubMedCentral

101.

Zhang H, Nimmer PM, Tahir SK, Chen J, Fryer RM, Hahn KR, Iciek LA, Morgan SJ, Nasarre MC, Nelson R, Preusser LC, Reinhart GA, Smith ML, Rosenberg SH, Elmore SW, Tse C: Bcl-2 family proteins are essential for platelet survival. Cell Death Differ. 2007, 14 (5): 943-951.PubMed

102.

Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML: ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013, 19 (2): 202-208. 10.1038/nm.3048.PubMed

103.

Vandenberg CJ, Cory S: ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia. Blood. 2013, 121 (12): 2285-2288. 10.1182/blood-2013-01-475855.PubMedPubMedCentral

104.

Cohen NA, Stewart ML, Gavathiotis E, Tepper JL, Bruekner SR, Koss B, Opferman JT, Walensky LD: A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. Chem Biol. 2012, 19 (9): 1175-1186. 10.1016/j.chembiol.2012.07.018.PubMedPubMedCentral

105.

Gautier F, Guillemin Y, Cartron PF, Gallenne T, Cauquil N, Le Diguarher T, Casara P, Vallette FM, Manon S, Hickman JA, Geneste O, Juin P: Bax activation by engagement with, then release from, the BH3 binding site of Bcl-xL. Mol Cell Biol. 2011, 31 (4): 832-844. 10.1128/MCB.00161-10.PubMedPubMedCentral

106.

Lessene G, Czabotar PE, Sleebs BE, Zobel K, Lowes KN, Adams JM, Baell JB, Colman PM, Deshayes K, Fairbrother WJ, Flygare JA, Gibbons P, Kersten WJ, Kulasegaram S, Moss RM, Parisot JP, Smith BJ, Street IP, Yang H, Huang DC, Watson KG: Structure-guided design of a selective BCL-X(L) inhibitor. Nat Chem Biol. 2013, 9 (6): 390-397. 10.1038/nchembio.1246.PubMed

107.

Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A: BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell. 2007, 12 (2): 171-185. 10.1016/j.ccr.2007.07.001.PubMed

108.

Ryan J, Letai A: BH3 profiling in whole cells by fluorimeter or FACS. Methods. 2013, 61 (2): 156-164. 10.1016/j.ymeth.2013.04.006.PubMedPubMedCentral

109.

Renault TT, Elkholi R, Bharti A, Chipuk JE: BH3 mimetics demonstrate differential activities dependent upon the functional repertoire of pro- and anti-apoptotic BCL-2 family proteins. J Biol Chem. 2014

110.

Gavathiotis E, Reyna DE, Bellairs JA, Leshchiner ES, Walensky LD: Direct and selective small-molecule activation of proapoptotic BAX. Nat Chem Biol. 2012, 8 (7): 639-645. 10.1038/nchembio.995.PubMedPubMedCentral

111.

Del Gaizo MV, Brown JR, Certo M, Love TM, Novina CD, Letai A: Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 2007, 117 (1): 112-121. 10.1172/JCI28281.

112.

Bean GR, Ganesan YT, Dong Y, Takeda S, Liu H, Chan PM, Huang Y, Chodosh LA, Zambetti GP, Hsieh JJ, Cheng EH: PUMA and BIM are required for oncogene inactivation-induced apoptosis. Sci Signal. 2013, 6 (268): ra20-PubMedPubMedCentral

113.

Anvekar RA, Asciolla JJ, Missert DJ, Chipuk JE: Born to be alive: a role for the BCL-2 family in melanoma tumor cell survival, apoptosis, and treatment. Front Oncol. 2011, 1 (34):

114.

Tait SW, Green DR: Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010, 11 (9): 621-632. 10.1038/nrm2952.PubMed

115.

Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS, Danial NN, De Strooper B, Scorrano L: OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell. 2006, 126 (1): 177-189. 10.1016/j.cell.2006.06.025.PubMed

116.

Yamaguchi R, Lartigue L, Perkins G, Scott RT, Dixit A, Kushnareva Y, Kuwana T, Ellisman MH, Newmeyer DD: Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Mol Cell. 2008, 31 (4): 557-569. 10.1016/j.molcel.2008.07.010.PubMedPubMedCentral

117.

Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA, Korsmeyer SJ: A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell. 2002, 2 (1): 55-67. 10.1016/S1534-5807(01)00116-2.PubMed

118.

Segawa K, Kurata S, Yanagihashi Y, Brummelkamp TR, Matsuda F, Nagata S: Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science. 2014, 344 (6188): 1164-1168. 10.1126/science.1252809.PubMed

119.

Poon IK, Lucas CD, Rossi AG, Ravichandran KS: Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014, 14 (3): 166-180. 10.1038/nri3607.PubMedPubMedCentral

120.

Vempati UD, Han X, Moraes CT: Lack of cytochrome c in mouse fibroblasts disrupts assembly/stability of respiratory complexes I and IV. J Biol Chem. 2009, 284 (7): 4383-4391. 10.1074/jbc.M805972200.PubMedPubMedCentral

121.

Hao Z, Duncan GS, Chang CC, Elia A, Fang M, Wakeham A, Okada H, Calzascia T, Jang Y, You-Ten A, Yeh WC, Ohashi P, Wang X, Mak TW: Specific ablation of the apoptotic functions of cytochrome C reveals a differential requirement for cytochrome C and Apaf-1 in apoptosis. Cell. 2005, 121 (4): 579-591. 10.1016/j.cell.2005.03.016.PubMed

122.

Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X: Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997, 91 (4): 479-489. 10.1016/S0092-8674(00)80434-1.PubMed

123.

Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW: Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell. 1998, 94 (3): 339-352. 10.1016/S0092-8674(00)81477-4.PubMed

124.

Honarpour N, Du C, Richardson JA, Hammer RE, Wang X, Herz J: Adult Apaf-1-deficient mice exhibit male infertility. Dev Biol. 2000, 218 (2): 248-258. 10.1006/dbio.1999.9585.PubMed

125.

Scott CL, Schuler M, Marsden VS, Egle A, Pellegrini M, Nesic D, Gerondakis S, Nutt SL, Green DR, Strasser A: Apaf-1 and caspase-9 do not act as tumor suppressors in myc-induced lymphomagenesis or mouse embryo fibroblast transformation. J Cell Biol. 2004, 164 (1): 89-96. 10.1083/jcb.200310041.PubMedPubMedCentral

126.

Soengas MS, Alarcon RM, Yoshida H, Giaccia AJ, Hakem R, Mak TW, Lowe SW: Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science. 1999, 284 (5411): 156-159. 10.1126/science.284.5411.156.PubMed

127.

Egle A, Harris AW, Bouillet P, Cory S: Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci U S A. 2004, 101 (16): 6164-6169. 10.1073/pnas.0401471101.PubMedPubMedCentral

128.

Frenzel A, Labi V, Chmelewskij W, Ploner C, Geley S, Fiegl H, Tzankov A, Villunger A: Suppression of B-cell lymphomagenesis by the BH3-only proteins Bmf and Bad. Blood. 2010, 115 (5): 995-1005. 10.1182/blood-2009-03-212670.PubMedPubMedCentral

129.

Salvesen GS, Abrams JM: Caspase activation—stepping on the gas or releasing the brakes? Lessons from humans and flies. Oncogene. 2004, 23 (16): 2774-2784. 10.1038/sj.onc.1207522.PubMed

130.

Eckelman BP, Salvesen GS, Scott FL: Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 2006, 7 (10): 988-994. 10.1038/sj.embor.7400795.PubMedPubMedCentral

131.

Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R: A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell. 2001, 8 (3): 613-621. 10.1016/S1097-2765(01)00341-0.PubMed

132.

Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL: Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000, 102 (1): 43-53. 10.1016/S0092-8674(00)00009-X.PubMed

133.

Okada H, Suh WK, Jin J, Woo M, Du C, Elia A, Duncan GS, Wakeham A, Itie A, Lowe SW, Wang X, Mak TW: Generation and characterization of Smac/DIABLO-deficient mice. Mol Cell Biol. 2002, 22 (10): 3509-3517. 10.1128/MCB.22.10.3509-3517.2002.PubMedPubMedCentral

134.

Kempkensteffen C, Hinz S, Christoph F, Krause H, Magheli A, Schrader M, Schostak M, Miller K, Weikert S: Expression levels of the mitochondrial IAP antagonists Smac/DIABLO and Omi/HtrA2 in clear-cell renal cell carcinomas and their prognostic value. J Cancer Res Clin Oncol. 2008, 134 (5): 543-550. 10.1007/s00432-007-0317-7.PubMed

135.

Mizutani Y, Nakanishi H, Yamamoto K, Li YN, Matsubara H, Mikami K, Okihara K, Kawauchi A, Bonavida B, Miki T: Downregulation of Smac/DIABLO expression in renal cell carcinoma and its prognostic significance. J Clin Oncol. 2005, 23 (3): 448-454.PubMed

136.

Sekimura A, Konishi A, Mizuno K, Kobayashi Y, Sasaki H, Yano M, Fukai I, Fujii Y: Expression of Smac/DIABLO is a novel prognostic marker in lung cancer. Oncol Rep. 2004, 11 (4): 797-802.PubMed

137.

Hofmann HS, Simm A, Hammer A, Silber RE, Bartling B: Expression of inhibitors of apoptosis (IAP) proteins in non-small cell human lung cancer. J Cancer Res Clin Oncol. 2002, 128 (10): 554-560. 10.1007/s00432-002-0364-z.PubMed

138.

Espinosa M, Cantu D, Lopez CM, De la Garza JG, Maldonado VA, Melendez-Zajgla J: SMAC is expressed de novo in a subset of cervical cancer tumors. BMC Cancer. 2004, 4: 84-10.1186/1471-2407-4-84.PubMedPubMedCentral

139.

Khodjakov A, Rieder C, Mannella CA, Kinnally KW: Laser micro-irradiation of mitochondria: is there an amplified mitochondrial death signal in neural cells?. Mitochondrion. 2004, 3 (4): 217-227. 10.1016/j.mito.2003.10.002.PubMed

140.

Harlin H, Reffey SB, Duckett CS, Lindsten T, Thompson CB: Characterization of XIAP-deficient mice. Mol Cell Biol. 2001, 21 (10): 3604-3608. 10.1128/MCB.21.10.3604-3608.2001.PubMedPubMedCentral

141.

Lamkanfi M, Declercq W, Vanden Berghe T, Vandenabeele P: Caspases leave the beaten track: caspase-mediated activation of NF-kappaB. J Cell Biol. 2006, 173 (2): 165-171. 10.1083/jcb.200509092.PubMedPubMedCentral

142.

Woo M, Hakem R, Furlonger C, Hakem A, Duncan GS, Sasaki T, Bouchard D, Lu L, Wu GE, Paige CJ, Mak TW: Caspase-3 regulates cell cycle in B cells: a consequence of substrate specificity. Nat Immunol. 2003, 4 (10): 1016-1022. 10.1038/ni976.PubMed

143.

Zandy AJ, Lakhani S, Zheng T, Flavell RA, Bassnett S: Role of the executioner caspases during lens development. J Biol Chem. 2005, 280 (34): 30263-30272. 10.1074/jbc.M504007200.PubMed

144.

Zermati Y, Garrido C, Amsellem S, Fishelson S, Bouscary D, Valensi F, Varet B, Solary E, Hermine O: Caspase activation is required for terminal erythroid differentiation. J Exp Med. 2001, 193 (2): 247-254. 10.1084/jem.193.2.247.PubMedPubMedCentral

145.

Fernando P, Kelly JF, Balazsi K, Slack RS, Megeney LA: Caspase 3 activity is required for skeletal muscle differentiation. Proc Natl Acad Sci U S A. 2002, 99 (17): 11025-11030. 10.1073/pnas.162172899.PubMedPubMedCentral

146.

Devarajan E, Sahin AA, Chen JS, Krishnamurthy RR, Aggarwal N, Brun AM, Sapino A, Zhang F, Sharma D, Yang XH, Tora AD, Mehta K: Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. Oncogene. 2002, 21 (57): 8843-8851. 10.1038/sj.onc.1206044.PubMed

147.

Yoo NJ, Lee JW, Kim YJ, Soung YH, Kim SY, Nam SW, Park WS, Lee JY, Lee SH: Loss of caspase-2, -6 and -7 expression in gastric cancers. APMIS. 2004, 112 (6): 330-335. 10.1111/j.1600-0463.2004.t01-1-apm1120602.x.PubMed

148.

Palmerini F, Devilard E, Jarry A, Birg F, Xerri L: Caspase 7 downregulation as an immunohistochemical marker of colonic carcinoma. Hum Pathol. 2001, 32 (5): 461-467. 10.1053/hupa.2001.24328.PubMed

149.

Lakhani SA, Masud A, Kuida K, Porter GA, Booth CJ, Mehal WZ, Inayat I, Flavell RA: Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science. 2006, 311 (5762): 847-851. 10.1126/science.1115035.PubMedPubMedCentral

150.

Gdynia G, Grund K, Eckert A, Bock BC, Funke B, Macher-Goeppinger S, Sieber S, Herold-Mende C, Wiestler B, Wiestler OD, Roth W: Basal caspase activity promotes migration and invasiveness in glioblastoma cells. Mol Cancer Res. 2007, 5 (12): 1232-1240. 10.1158/1541-7786.MCR-07-0343.PubMed

151.

Zhou H, Li XM, Meinkoth J, Pittman RN: Akt regulates cell survival and apoptosis at a postmitochondrial level. J Cell Biol. 2000, 151 (3): 483-494. 10.1083/jcb.151.3.483.PubMedPubMedCentral

152.

Deshmukh M, Johnson EM: Evidence of a novel event during neuronal death: development of competence-to-die in response to cytoplasmic cytochrome c. Neuron. 1998, 21 (4): 695-705. 10.1016/S0896-6273(00)80587-5.PubMed

153.

Martinou I, Desagher S, Eskes R, Antonsson B, Andre E, Fakan S, Martinou JC: The release of cytochrome c from mitochondria during apoptosis of NGF-deprived sympathetic neurons is a reversible event. J Cell Biol. 1999, 144 (5): 883-889. 10.1083/jcb.144.5.883.PubMedPubMedCentral

154.

Potts MB, Vaughn AE, McDonough H, Patterson C, Deshmukh M: Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP. J Cell Biol. 2005, 171 (6): 925-930. 10.1083/jcb.200504082.PubMedPubMedCentral

155.

Potts PR, Singh S, Knezek M, Thompson CB, Deshmukh M: Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis. J Cell Biol. 2003, 163 (4): 789-799. 10.1083/jcb.200307130.PubMedPubMedCentral

156.

Wright KM, Linhoff MW, Potts PR, Deshmukh M: Decreased apoptosome activity with neuronal differentiation sets the threshold for strict IAP regulation of apoptosis. J Cell Biol. 2004, 167 (2): 303-313. 10.1083/jcb.200406073.PubMedPubMedCentral

157.

Jia L, Srinivasula SM, Liu FT, Newland AC, Fernandes-Alnemri T, Alnemri ES, Kelsey SM: Apaf-1 protein deficiency confers resistance to cytochrome c-dependent apoptosis in human leukemic cells. Blood. 2001, 98 (2): 414-421. 10.1182/blood.V98.2.414.PubMed

158.

Krepela E, Prochazka J, Fiala P, Zatloukal P, Selinger P: Expression of apoptosome pathway-related transcripts in non-small cell lung cancer. J Cancer Res Clin Oncol. 2006, 132 (1): 57-68. 10.1007/s00432-005-0048-6.PubMed

159.

Watanabe T, Hirota Y, Arakawa Y, Fujisawa H, Tachibana O, Hasegawa M, Yamashita J, Hayashi Y: Frequent LOH at chromosome 12q22-23 and Apaf-1 inactivation in glioblastoma. Brain Pathol. 2003, 13 (4): 431-439.PubMed

160.

Wolf BB, Schuler M, Li W, Eggers-Sedlet B, Lee W, Tailor P, Fitzgerald P, Mills GB, Green DR: Defective cytochrome c-dependent caspase activation in ovarian cancer cell lines due to diminished or absent apoptotic protease activating factor-1 activity. J Biol Chem. 2001, 276 (36): 34244-34251. 10.1074/jbc.M011778200.PubMed

161.

Yang L, Mashima T, Sato S, Mochizuki M, Sakamoto H, Yamori T, Oh-Hara T, Tsuruo T: Predominant suppression of apoptosome by inhibitor of apoptosis protein in non-small cell lung cancer H460 cells: therapeutic effect of a novel polyarginine-conjugated Smac peptide. Cancer Res. 2003, 63 (4): 831-837.PubMed

162.

Fujita E, Jinbo A, Matuzaki H, Konishi H, Kikkawa U, Momoi T: Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9. Biochem Biophys Res Commun. 1999, 264 (2): 550-555. 10.1006/bbrc.1999.1387.PubMed

163.

Colell A, Ricci JE, Tait S, Milasta S, Maurer U, Bouchier-Hayes L, Fitzgerald P, Guio-Carrion A, Waterhouse NJ, Li CW, Mari B, Barbry P, Newmeyer DD, Beere HM, Green DR: GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell. 2007, 129 (5): 983-997. 10.1016/j.cell.2007.03.045.PubMed

164.

Tait SW, Parsons MJ, Llambi F, Bouchier-Hayes L, Connell S, Munoz-Pinedo C, Green DR: Resistance to caspase-independent cell death requires persistence of intact mitochondria. Dev Cell. 2010, 18 (5): 802-813. 10.1016/j.devcel.2010.03.014.PubMedPubMedCentral

165.

Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y: Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature. 2000, 406 (6798): 855-862. 10.1038/35022514.PubMed

166.

Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC, Fesik SW: Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature. 2000, 408 (6815): 1004-1008. 10.1038/35050006.PubMed

167.

Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y: Structural basis of IAP recognition by Smac/DIABLO. Nature. 2000, 408 (6815): 1008-1012. 10.1038/35050012.PubMed

168.

Chen DJ, Huerta S: Smac mimetics as new cancer therapeutics. Anticancer Drugs. 2009, 20 (8): 646-658. 10.1097/CAD.0b013e32832ced78.PubMed

169.

Greer RM, Peyton M, Larsen JE, Girard L, Xie Y, Gazdar AF, Harran P, Wang L, Brekken RA, Wang X, Minna JD: SMAC mimetic (JP1201) sensitizes non-small cell lung cancers to multiple chemotherapy agents in an IAP-dependent but TNF-alpha-independent manner. Cancer Res. 2011, 71 (24): 7640-7648. 10.1158/0008-5472.CAN-10-3947.PubMedPubMedCentral

170.

Dineen SP, Roland CL, Greer R, Carbon JG, Toombs JE, Gupta P, Bardeesy N, Sun H, Williams N, Minna JD, Brekken RA: Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer. Cancer Res. 2010, 70 (7): 2852-2861. 10.1158/0008-5472.CAN-09-3892.PubMedPubMedCentral

171.

Micheau O, Tschopp J: Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003, 114 (2): 181-190. 10.1016/S0092-8674(03)00521-X.PubMed

172.

Carter BZ, Mak DH, Morris SJ, Borthakur G, Estey E, Byrd AL, Konopleva M, Kantarjian H, Andreeff M: XIAP antisense oligonucleotide (AEG35156) achieves target knockdown and induces apoptosis preferentially in CD34 + 38- cells in a phase 1/2 study of patients with relapsed/refractory AML. Apoptosis. 2011, 16 (1): 67-74. 10.1007/s10495-010-0545-1.PubMedPubMedCentral

Title: Putting the pieces together: How is the mitochondrial pathway of apoptosis regulated in cancer and chemotherapy?
Authors: Rana Elkholi
Thibaud T Renault
Madhavika N Serasinghe
Jerry E Chipuk
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Cancer & Metabolism / Issue 1/2014
Electronic ISSN: 2049-3002
DOI: https://doi.org/10.1186/2049-3002-2-16

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