Programmed Cell Death in Cancer Cells

Czech version

Authors: E. Ondroušková; B. Vojtěšek
Authors‘ workplace: Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno
Published in: Klin Onkol 2014; 27(Supplementum): 7-14

Overview

Resistance to programmed cell death is one of the hallmarks of cancer cells that affects the process of malignant transformation as well as response to cancer therapy. The goal of this review is to summarize recent information about programmed cell death (PCD) in healthy and cancer cells, as well as new perspectives for anticancer treatments targeting these signaling pathways. Three main types of PCD are described in detail: apoptosis, necrosis/ necroptosis and cell death associated with autophagy. Among them, apoptosis plays the key role in both malignant transformation and response to therapy. In this review, we describe main signaling pathways and molecules participating in apoptosis regulation in healthy cells. In most cancer cells, mutations or aberrant expression of proteins directly or indirectly involved in induction and execution of cell death can be detected – p53, Bcl‑ 2 family proteins, inhibitors of apoptosis, death receptors/ ligands and other proteins. Mutations or changes in expression of these proteins and their relation to certain types of tumors are described. Finally, we provide a review of recently developed treatments that target and reactivate the machinery of programmed cell death and are currently tested in clinical trials.

Key words:
programmed cell death – apoptosis – necroptosis – autophagy – caspases – Bcl‑ 2

This work was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) and by MH CZ – DRO (MMCI, 00209805).

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Submitted:
14. 1. 2014

Accepted:
6. 3. 2014

Sources

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

2. Kroemer G, Galluzzi L, Vandenabeele P et al. Classification of cell death: recommendation of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 2009; 16(1): 3– 11. doi: 10.1038/ cdd.2008.150.

3. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide‑ ranging implications in tissue kinetics. Br J Cancer 1972; 26(4): 239– 257.

4. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 2005; 6(4): 328– 340.

5. Rubinstein AD, Kimchi A. Life in the balance – a mechanistic view of the crosstalk between autophagy and apoptosis. J Cell Sci 2012; 125(Pt 22): 5259– 5268. doi: 10.1242/ jcs.115865.

6. Martinet W, Schrijvers DM, Herman AG et al. Z‑ VAD‑ fmk induced non‑apoptotic cell death of macrophages. Autophagy 2006; 2(4): 312– 314.

7. Kerr JF, Winterford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer therapy. Cancer 1994; 73(8): 2013– 2026.

8. Fadok VA, Bratton DL, Frasch SC et al. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ 1998; 5(7): 551– 562.

9. Ashkenazi A, Dixit VM. Death receptors: Signaling and modulation. Science 1998; 281(5381): 1305– 1308.

10. Wachman K, Pop C, van Raam BJ et al. Activation and specifity of human caspase‑ 10. Biochemistry 2010; 49(38): 8307– 8315. doi: 10.1021/ bi100968m.

11. Michalak EM, Villunger A, Adams JM et al. In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death Differ 2008; 15(6): 1019– 1029. doi: 10.1038/ cdd.2008.16.

12. Goh AM, Coffill CR, Lane DP. The role of mutant p53 in human cancer. J Pathol 2011; 223(2): 116– 126. doi: 10.1002/ path.2784.

13. Amaral JD, Xavier JM, Steer CJ et al. The role of p53 in apoptosis. Discov Med 2010; 9(45): 145– 152.

14. Burlacu A. Regulation of apoptosis by Bcl‑ 2 family proteins. J Cell Mol Med 2003; 7(3): 249– 257.

15. Chipuk JE, Kuwana T, Bouchier‑ Hayes L et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004; 303(5660): 1010– 1014.

16. Chipuk JE, Moldoveanu T, Llambi F et al. The Bcl‑ 2 family reunion. Molecular Cell 2010; 37(3): 299– 310. doi: 10.1016/ j.molcel.2010.01.025.

17. Sedlak TW, Oltvai ZN, Yang E et al. Multiple Bcl‑ 2 family members demonstrate selective dimerizations with Bax. Proc Natl Acad Sci USA 1995; 92(17): 7834– 7838.

18. Vela L, Gonzalo O, Naval J et al. Direct interaction of Bax and Bak proteins with Bcl‑ 2 homology domain 3(BH3)- only proteins in living cells revealed by fluorescence complementation. J Biol Chem 2013; 288(7): 4935– 4946. doi: 10.1074/ jbc.M112.422204.

19. Kluck RM, Bossy‑ Wetzel E, Green DR et at. The release of cytochrome c from mitochondria: A primary site for Bcl‑ 2 regulation of apoptosis. Science 1997; 275(5303): 1132– 1136.

20. Zou H, Henzel WJ, Liu A et al. Apaf‑ 1, a human protein homologous to C. elegans CED‑ 4, participates in cytochrome c‑ dependent activation of caspase‑ 3. Cell 1997; 90(3): 405– 413.

21. Deveraux QL, Reed JC. IAP family proteins – suppressors of apoptosis. Genes Dev 1999; 13(3): 239– 252.

22. Du C, Fang M, Li Y et al. Smac, a mitochondrial protein that promotes cytochrome c‑ dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102(1): 33– 42.

23. Gottfried Y, Rotem A, Lotan R et al. The mitochondrial ARTS protein promotes apoptosis through targeting XIAP. EMBO J 2004; 23(7): 1627– 1635.

24. Schafer P, Scholz SR, Gimadutdinow O et al. Structural and functional characterization of mitochondrial EndoG, a sugar non‑specific nuclease which plays an important role during apoptosis. J Mol Biol 2004; 338(2): 217– 228.

25. Nakagawa T, Zhu H, Morishima N et al. Caspase‑ 12 mediates endoplasmic‑ reticulum‑ specific apoptosis and cytotoxicity by amyloid‑beta. Nature 2000; 403(6765): 98– 103.

26. Beneš P, Větvička V, Fusek M. Cathepsin D – many functions of one aspartic protease. Crit Rev Oncol Hematol 2008; 68(1): 12– 28. doi: 10.1016/ j.critrevonc.2008.02.008.

27. Guicciardi ME, Leist M, Gores GJ. Lysosomes in cell death. Oncogene 2004; 23(16): 2881– 2890.

28. Fisher U, Janicke RU, Schulze‑ Osthoff K. Many cuts to ruin: a comprehensive update of caspase substrates. Cell Death Differ 2003; 10(1): 76– 100.

29. de Duve CH, Wattiaux R. Functions of lysosome. Annu Rev Physiol 1966; 28: 435– 492.

30. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell 2011; 147(4): 728– 741. doi: 10.1016/ j.cell.2011.10.026.

31. Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol 2010; 12(9): 814– 822. doi: 10.1038/ ncb0910- 814.

32. Rosenfeldt MT, Ryan KM. The multiple roles of autophagy in cancer. Carcinogenesis 2011; 32(7): 955– 963. doi: 10.1093/ carcin/ bgr031.

33. Esposti DD, Domart MC, Sebagh M et al. Autophagy is induced by ischemic preconditioning in human livers formerly treated by chemotherapy to limit necrosis. Autophagy 2010; 6(1): 172– 174.

34. Mathew R, Kongara S, Beaudoin B et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 2007; 21(11): 1367– 1381.

35. Yang S, Wang X, Contino G et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev 2011; 25(7): 717– 729. doi: 10.1101/ gad.2016111.

36. Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest 2005; 115(10): 2679– 2688.

37. Berry DL, Baehrecke EH. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 2007; 131(6): 1137– 1148.

38. Degterev A, Huang Z, Boyce M et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 2005; 1(2): 112– 119.

39. Vanlangenakker N, Bertrand MJM, Bogaert P et al. TNF‑induced necroptosis in L929 cells is tightly regulated by multiple TNFR1 complex I and II members. Cell Death Dis 2011; 2(11): e230. doi: 10.1038/ cddis.2011.111.

40. Scaffidi C, Kirchhoff S, Krammer PH et al. Apoptosis signaling in lymphocytes. Curr Opin Immunol 1999; 11(3): 277– 285.

41. Degterev A, Hitomi J, Germscheid M et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 2008; 4(5): 313– 321. doi: 10.1038/ nchembio.83.

42. Hayden MS, Ghosh S. Shared principles in NF‑ kappaB signaling. Cell 2008: 132(3): 344– 362. doi: 10.1016/ j.cell.2008.01.020.

43. Ouyang L, Shi Z, Zhao S et al. Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 2012; 45(6): 478– 498. doi: 10.1111/ j.1365- 2184.2012.00845.x.

44. Zhang DW, Shao J, Lin J et al. RIP3, an energy metabolism regulator that switches TNF‑induced cell death from apoptosis to necrosis. Science 2009; 325(5938): 332– 336. doi: 10.1126/ science.1172308.

45. Lin Y, Choksi S, Shen HM et al. Tumor necrosis factor‑induced nonapoptotic cell death requires receptor‑ interacting protein‑mediated cellular reactive oxygen species accumulation. J Biol Chem 2004; 279(11): 10822– 10828.

46. Vandenabeele P, Galluzzi L, Vanden Berghe T et al. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 2010; 11(10): 700– 714. doi: 10.1038/ nrm2970.

47. Natoli G, Ianni A, Constanzo A et al. Resistance to Fas‑ mediated apoptosis in human hepatoma cells. Oncogene 1995; 11(6): 1157– 1164.

48. Irmler M, Thome M, Hahne M et al. Inhibition of death receptor signals by cellular FLIP. Nature 1997; 388(6638): 190– 195.

49. Rieux‑ Laucat F, Le Deist F, Hivroz C et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimunity. Science 1995; 268(5215): 1347– 1349.

50. Landowsky TH, Qu N, Buyuksal I et al. Mutations in the Fas antigen in patients with multiple myeloma. Blood 1997; 90(11): 4266– 4270.

51. Gronbaek K, Straten PT, Ralfkiaer E et al. Somatic Fas mutations in non‑Hodgkin‘s lymphoma: association with extranodal disease and autoimmunity. Blood 1998; 92(9): 3018– 3024.

52. Bin L, Thorburn J, Thomas LR et al. Tumor‑ derived mutations in the TRAIL receptor DR5 inhibit TRAIL signaling through the DR4 receptor by competing for ligand binding. J Biol Chem 2007; 282(38): 28189– 28194.

53. Lee SH, Shin MS, Kim HS et al. Alterations of the DR5/ TRAIL receptor 2 gene in non‑small cell lung cancers. Cancer Res 1999; 59(22): 5683– 5686.

54. Shin MS, Kim HS, Lee SH et al. Mutations of tumor necrosis factor‑related apoptosis‑ inducing ligand receptor 1(TRAIL‑R1) and receptor 2 (TRAIL‑R2) genes in metastatic breast cancers. Cancer Res 2001; 61(13): 4942– 4946.

55. Fisher MJ, Virmani LW, Aplenc R et al. Nucleotide substitution in the ectodomain of TRAIL receptor DR4 is associated with lung cancer and head and neck cancer. Clin Cancer Res; 7(6): 1688– 1697.

56. Tsujimoto Y, Gorham J, Cossman J et al. The t(14;18) chromosome translocations involved in B‑ cell neoplasms result from mistakes in VDJ joining. Science 1985; 229(4720): 1390– 1393.

57. Kelly PN, Strasser A. The role of Bcl‑ 2 and its pro‑survival relatives in tumourigenesis and cancer therapy. Cell Death Differ 2011; 18(9): 1414– 1424. doi: 10.1038/ cdd.2011.17.

58. Krajewski S, Krajewska M, Shabaik A et al. Immunohistochemical analysis of in vivo patterns of Bcl‑ X expression. Cancer Res 1994; 54(21): 5501– 5507.

59. Beroukhim R, Mermel C, Porter D et al. The landscape of somatic copy‑ number alteration across human cancers. Nature 2010; 463(7283): 899– 905. doi: 10.1038/ nature08822.

60. Tagawa H, Karnan S, Suzuki R et al. Genome‑ wide array‑based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene 2005; 24(8): 1348– 1358.

61. Garrison SP, Jeffers JR, Yang C et al. Selection against PUMA gene expression in Myc‑driven B‑ cell lymphomagenesis. Mol Cell Biol 2008; 28(17): 5391– 5402. doi: 10.1128/ MCB.00907- 07.

62. Rampino N, Yamamoto H, Ionov Y et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275(5302): 967– 969.

63. Meijerink JP, Smetsers TF, Sloetjes AW et al. Bax mutations in cell lines derived from hematological malignancies. Leukemia 1995; 9(11): 1828– 1832.

64. Soengas MS, Capoieci P, Polsky D et al. Inactivation of the apoptosis effector Apaf‑ 1 in malignant melanoma. Nature 2001; 409(6817): 207– 211.

65. Sturm I, Bosanquet AG, Radetzki S et al. Silencing of Apaf‑ 1 in B‑ CLL results in poor prognosis in the case of concomitant p53 mutation. Int J Cancer 2006; 118(9): 2329– 2336.

66. Dubrez L, Berthelet J, Glorian V. IAP proteins as target for drug development in oncology. Onco Targets Ther 2013; 6: 1285– 1304.

67. Garrison JB, Samuel T, Reed JC. TRAF2‑binding BIR1 domain of c‑ IAP2/ MALT1 fusion protein is essential for activation of NF‑ kappaB. Oncogene 2009; 28(13): 1584– 1593. doi: 10.1038/ onc.2009.17.

68. Annunziata CM, Davis RE, Demchenko Y et al. Frequent engagement of the classical and alternative NF‑ kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 2007; 12(2): 115– 130.

69. Filipovich AH, Zhang K, Snow AL et al. X‑linked lymphoproliferative syndromes: brothers or distant cousins? Blood 2010; 116(18): 3398– 3408. doi: 10.1182/ blood‑ 2010- 03- 275909.

70. Soung YH, Lee JW, Kim SY et al. Caspase‑ 8 gene is inactivated by somatic mutations in gastric carcinomac. Cancer Res 2005; 65(3): 815– 821.

71. Martinez R, Setien F, Voelter C et al. CpG island promoter hypermethylation of the pro‑apoptotic gene caspase‑ 8 is a common hallmark of relapsed glioblastoma multiforme. Carcinogenesis 2007; 28(6): 1264– 1268.

72. Soung YH, Lee JW, Kim SY et al. Somatic mutations of CASP3 gene in human cancers. Hum Genet 2004; 115(2): 112– 115.

73. Soung YH, Lee JW, Kim HS et al. Inactivating mutations of CASPASE‑ 7 gene in human cancers. Oncogene 2003; 22(39): 8048– 8052.

74. Chen K, Zhao H, Hu Z et al. CASP3 polymorphisms and risk of squamous cell carcinoma of the head and neck. Clin Cancer Res 2008; 14(19): 6343– 6349. doi: 10.1158/ 1078- 0432.CCR‑ 08- 1198.

75. Olsson M, Zhivotovsky B. Caspases and cancer. Cell Death Differ 2011; 18(9): 1441– 1449. doi: 10.1038/ cdd.2011.30.

76. Greco FA, Bonomi P, Crawford J et al. Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor‑ 1 in patients with advanced non‑small cell lung cancer. Lung Cancer 2008; 61(1): 82– 90. doi: 10.1016/ j.lungcan.2007.12.011.

77. Zhang I, Zhang X, Barrisford GE et al. Lexatumumab (TRAIL‑receptor 2 mAb) induces expression of DR5 and promotes apoptosis in primary and metastatic renal cell carcinoma in a mouse orthotopic model. Cancer Lett 2007; 251 (1): 146– 157.

78. Zinonos I, Labrinidis A, Lee M et al. Apomab, a fully human agonistic antibody to DR5, exhibits potent antitumor activity against primary and metastatic breast cancer. Mol Cancer Ther 2009; 8(10): 2969– 2980. doi: 10.1158/ 1535- 7163.MCT‑ 09- 0745.

79. Soria JC, Mark Z, Zatloukal P et al. Randomized phase IIstudy of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non‑small cell lung cancer. J Clin Oncol 2011; 29(33): 4442– 4451. doi: 10.1200/ JCO.2011.37.2623.

80. Jia LT, Zhang LH, Yu CJ et al. Specific tumoricidal activity of a secreted proapoptotic protein consisting of HER2 antibody and constitutively active caspase‑ 3. Cancer Res 2003; 63(12): 3257– 3262.

81. Shariat SF, Desai S, Song W et al. Adenovirus‑ mediated transfer of inducible caspases: a novel „death switch“ gene therapeutic approach to prostate cancer. Cancer Res 2001; 61(6): 2562– 2571.

82. Tanioka M, Nokihara H, Yamamoto N et al. Phase Istudy of LY2181308, an antisense oligonucleotide against survivin, in patients with advanced solid tumors. Cancer Chemother Pharmacol 2011; 68(2): 505– 511. doi: 10.1007/ s00280- 010- 1506- 7.

83. Schimmer AD, Estey EH, Borthakur G et al. Phase I/ II trial of AEG35156 X‑linked inhibitor of apoptosis protein antisense oligonucleotide combined with idarubicin and cytarabine in patients with relapsed or primary refractory acute myeloid leukemia. J Clin Oncol 2009; 27(28): 4741– 4746. doi: 10.1200/ JCO.2009.21.8172.

84. Gyrd‑ Hansen M, Meier P. IAPs: from caspase inhibitors to modulators of NF‑ κB, inflammation and cancer. Nat Rev Cancer 2010; 10(8): 561– 574. doi: 10.1038/ /nrc2889.

85. Qin Q, Zuo Y, Yang X et al. Smac mimetic compound LCL161 sensitizes esophageal carcinoma cells to radiotherapy by inhibiting the expression of inhibitor of apoptosis protein. Tumor Biol 2014; 35(3): 2565– 2574. doi: 10.1007/ s13277- 013- 1338-2.

86. O‘Brien S, Moore JO, Boyd TE et al. 5‑year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol 2009; 27(31): 5208– 5212. doi: 10.1200/ JCO.2009.22.5748.

87. Goard CA, Schimmer AD. An evidence‑based review of obatoclax mesylate in the treatment of hematological malignancies. Core Evid 2013; 8: 15– 26. doi: 10.2147/ CE.S42568.

88. Baggstrom MQ, Qi Y, Koczywas M et al. A phase IIstudy of AT‑ 101 (Gossypol) in chemotherapy‑ sensitive recurrent extensive‑stage small cell lung cancer. J Thorac Oncol 2011; 6(10): 1757– 1760. doi: 10.1097/ JTO.0b013e31822e2941.

89. Rudin CM, Hann CL, Garon EB et al. Phase II study of single‑agent navitoclax (ABT‑ 263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 2012; 18(11): 3163– 3169. doi: 10.1158/ 1078- 0432.CCR‑ 11- 3090.

90. Chaabane W, User SD, El‑ Gazzah M et al. Autophagy, apoptosis, mitoptosis and necrosis: interdependence between those pathways and effects on cancer. Arch Immunol Ther Exp 2013; 61(1): 43– 58. doi: 10.1007/ s00005- 012- 0205- y.

91. Ondroušková E, Souček K, Horváth V et al. Alternative pathways of programmed cell death are activated in cells with defective caspase‑ dependent apoptosis. Leuk Res 2008; 32(4): 599– 609.

92. Walker NI, Harmon BV, Gobé GC et al. Patterns of cell death. Methods Achiev Exp Pathol 1988; 13: 18– 54.

93. Brown M, Wilson G. Apoptosis genes and resistance to cancer therapy. Cancer Biol Ther 2003; 2(5): 477– 490.