Skip to main content

Advertisement

Log in

Major apoptotic mechanisms and genes involved in apoptosis

  • Review
  • Published:
Tumor Biology

Abstract

As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2013;35:495–516.

    Article  CAS  Google Scholar 

  2. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis. 2000;21:485–95.

    Article  CAS  PubMed  Google Scholar 

  4. Horvitz HR. Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res. 1999;59:1701–6.

    Google Scholar 

  5. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;10:1456–62.

    Article  Google Scholar 

  6. Krauss G. Biochemistry of signal transduction and regulation. Ed:VCH Wiley, 3rd Edition. 2003;511–531.

  7. Power C, Fanning N, Redmond HP. Cellular apoptosis and organ injury in sepsis: a review. Shoch. 2002;18:197–211.

    Article  Google Scholar 

  8. Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature. 2000;407:784–8.

    Article  CAS  PubMed  Google Scholar 

  9. Rosenblatt J, Raff MC, Cramer LP. An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr Biol. 2011;11:1847–57.

    Article  Google Scholar 

  10. Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol. 2001;3:255–63.

    Article  CAS  Google Scholar 

  11. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995;146:3–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu X, Li P, Widlak P, et al. The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis. Proc Natl Acad Sci U S A. 1998;95:8461–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Grimsley C, Ravichandran KS. Cues for apoptotic cell engulfment: eat-me, don’t-eat-me and come-get-me signals. Trends Cell Biol. 2003;13:648–56.

    Article  CAS  PubMed  Google Scholar 

  14. Mashima T, Naito M, Noguchi K, Miller DK, Nicholson DW, Tsuruo T. Actin cleavage by CPP-32/apopain during the development of apoptosis. Oncogene. 1997;14:1007–12.

    Article  CAS  PubMed  Google Scholar 

  15. Ziegler U, Groscurth P. Morphological features of cell death. Physiology. 2004;10:124–8.

    Article  Google Scholar 

  16. Wang X. The expanding role of mitochondria in apoptosis. Genes Dev. 2001;15:2922–33.

    CAS  PubMed  Google Scholar 

  17. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science. 1998;281:1312–6.

    Article  CAS  PubMed  Google Scholar 

  18. Hengartnere MO. The biochemistry of apoptosis. Nature. 2000;407:770–6.

    Article  Google Scholar 

  19. Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin. 2005;55:178–94.

    Article  PubMed  Google Scholar 

  20. Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P. Toxic proteins released from mitochondria in cell death. Oncogene. 2004;23:2861–74.

    Article  CAS  PubMed  Google Scholar 

  21. Du C, Fang M, Li Y, Li L, Wang X. SMAC, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:33–42.

    Article  CAS  PubMed  Google Scholar 

  22. Chinnaiyan AM. The apoptosome: heart and soul of the cell death machine. Neoplasia. 1999;1:5–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hill MM, Adrain C, Duriez PJ, Creagh EM, Martin SJ. Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes. Embo J. 2004;23:2134–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Susin SA, Daugas E, Ravagnan L, et al. Two distinct pathways leading to nuclear apoptosis. J Exp Med. 2000;192:571–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002;2:647–56.

    Article  CAS  PubMed  Google Scholar 

  26. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104:487–501.

    Article  CAS  PubMed  Google Scholar 

  27. Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995;81:495–50.

    Article  CAS  PubMed  Google Scholar 

  28. Wajant H. The Fas signaling pathway: more than a paradigm. Science. 2002;296:1635–6.

    Article  CAS  PubMed  Google Scholar 

  29. Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS. BID regulation by p53 contributes to chemosensitivity. Nat Cell Biol. 2002;4:842–9.

    Article  CAS  PubMed  Google Scholar 

  30. Hitoshi Y, Lorens J, Kitada SI, et al. Toso, a cell surface, specific regulator of Fas-induced apoptosis in T cells. Immunity. 1998;8:461–71.

    Article  CAS  PubMed  Google Scholar 

  31. Scaffidi C, Schmitz I, Krammer PH, Peter ME. The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem. 1999;274:1541–8.

    Article  CAS  PubMed  Google Scholar 

  32. Kuranaga E. Beyond apoptosis: caspase regulatory mechanisms and functions in vivo. Genes Cells. 2012;17:83–97.

    Article  CAS  PubMed  Google Scholar 

  33. Yuan J, Shaham S, Ledoux S, Ellis HM, The HHR. The C. elegans cell death gene Ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993;75:641–52.

    Article  CAS  PubMed  Google Scholar 

  34. Ellis HM, Horvitz HR. Genetic control of programmed cell death in the nematode C. elegans. Cell. 1986;44:817–29.

    Article  CAS  PubMed  Google Scholar 

  35. Shi Y. Mechanisms of caspase inhibition and activation during apoptosis. Mol Cell. 2002;9:459–70.

    Article  CAS  PubMed  Google Scholar 

  36. Chowdhury I, Tharakan B, Bhat GK. Caspases—an update. Comp Biochem Physiol. 2008;151:10–27.

    Article  CAS  Google Scholar 

  37. Yan N, Shi Y. Mechanisms of apoptosis through structural biology. Annu Rev Cell Dev Biol. 2005;21:35–56.

    Article  CAS  PubMed  Google Scholar 

  38. Los M, Stroh C, Janicke RU, Schulze-Osthoff K. Caspases: more than just killers? Trends Immunol. 2001;22:31–4.

    Article  CAS  PubMed  Google Scholar 

  39. Martinon F, Tschopp J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell. 2004;117:561–74.

    Article  CAS  PubMed  Google Scholar 

  40. Los M, van de Craen M, Penning CL, et al. Requirement of an ICE/CED-3 protease for Fas/APO-1-1 mediated apoptosis. Nature. 1995;37:81–3.

    Article  Google Scholar 

  41. Fantuzzi G, Puren AJ, Harding MW, Livingston DJ, Dinarello CA. Interleukin-18 regulation of interferon gamma production and cell proliferation as shown in interleukin-1beta-converting enzyme (caspase-1)-deficient mice. Blood. 1998;91:2118–25.

    CAS  PubMed  Google Scholar 

  42. Vakifahmetoglu-Norberg H, Zhivotovsky B. The unpredictable caspase-2: what can it do? Trends Cell Biol. 2010;20:150–9.

    Article  CAS  PubMed  Google Scholar 

  43. Paroni G, Henderson C, Schneider C, Brancolini C. Caspase-2-induced apoptosis is dependent on caspase-9, but its processing during UV- or tumor necrosis factor-dependent cell death requires caspase-3. J Biol Chem. 2001;276:21907–15.

    Article  CAS  PubMed  Google Scholar 

  44. Van de Craen M, Declercq W. Van den brande I, Fiers W, Vandenabeele P. The proteolytic procaspase activation network: an in vitro analysis. Cell Death Differ. 1999;6:1117–24.

    Article  PubMed  CAS  Google Scholar 

  45. Tinel A, Tschopp J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science. 2004;304:843–6.

    Article  CAS  PubMed  Google Scholar 

  46. Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene. 2003;22:8543–67.

    Article  CAS  PubMed  Google Scholar 

  47. Porter AG, Janicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999;6:99–104.

    Article  CAS  PubMed  Google Scholar 

  48. Slee EA, Adrain C, Martin SJ. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem. 2001;276:7320–6.

    Article  CAS  PubMed  Google Scholar 

  49. Lakhani SA, Masud A, Kuida K, et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science. 2006;311:847–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lamkanfi M, Kanneganti TD. Caspase-7: a protease involved in apoptosis and inflammation. Int J Biochem Cell Biol. 2010;42:21–4.

    Article  CAS  PubMed  Google Scholar 

  51. Ghavami S, Eshraghi M, Kadkhoda K, et al. Role of BNIP3 in TNF-induced cell death—TNF upregulates BNIP3 expression. Biochim Biophys Acta. 1793;2009:546–60.

    Google Scholar 

  52. Carrington PE, Sandu C, Wei Y, et al. The structure of FADD and its mode of interaction with procaspase-8. Mol Cell. 2006;22:599–610.

    Article  CAS  PubMed  Google Scholar 

  53. Ghavami S, Hashemi M, Ande SR, et al. Apoptosis and cancer: mutations within caspase genes. J Med Genet. 2009;46:497–510.

    Article  CAS  PubMed  Google Scholar 

  54. Micheau O, Thome M, Schneider P, et al. Gr ̈utter MG. The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J Biol Chem. 2002;277:45162–71.

    Article  CAS  PubMed  Google Scholar 

  55. Irmler M, Thome M, Hahne M, et al. Inhibition of death receptors signals by cellular FLIP. Nature. 1997;388:190–5.

    Article  CAS  PubMed  Google Scholar 

  56. Boatright KM, Deis C, Denault JB, Sutherlin DP, Salvesen GC. Activation of caspases-8 and -10 by FLIP (L). Biochem J. 2004;382:651–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pop C, Oberst A, Drag M, et al. FLIP (L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity. Biochem J. 2011;433:447–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chang DW, Xing Z, Pan Y, et al. c-FLIP8(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J. 2002;21:3704–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rodriguez J, Lazebnik Y. Caspase-9 and APAF-1 form an active holoenzyme. Genes Dev. 1999;13:3179–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Qin H, Srinivasula SM, Wu G, Fernandes-Alnemri T, Alnemri ES, Shi Y. Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1. Nature. 1999;399:549–57.

    Article  CAS  PubMed  Google Scholar 

  61. Crook NE, Clem RJ, Miller LK. An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol. 1993;67:2168–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Kaiser WJ, Vucic D, Miller LK. The Drosophila inhibitor of apoptosis D-IAP1 suppresses cell death induced by the caspase drICE. FEBS Lett. 1998;440:243–8.

    Article  CAS  PubMed  Google Scholar 

  63. Eckelman BP, Salvesen GS. The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases. J Biol Chem. 2006;281:3254–60.

    Article  CAS  PubMed  Google Scholar 

  64. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997;3:917–22.

    Article  CAS  PubMed  Google Scholar 

  65. Banks DP, Plescia J, Altieri DC, et al. Survivin does not inhibit caspase-3 activity. Blood. 2000;96:4002–3.

    CAS  PubMed  Google Scholar 

  66. Saleem M, Qadir MI, Perveen N, et al. Inhibitors of apoptotic proteins: new targets for anticancer therapy. Chem Biol Drug Des. 2013;82:243–51.

    Article  CAS  PubMed  Google Scholar 

  67. Sun C, Cai M, Gunasekera AH, et al. NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP. Nature. 1999;401:818–21.

    Article  CAS  PubMed  Google Scholar 

  68. Sun CH, Cai ML, Meadows RP, et al. NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP. J Biol Chem. 2000;275:33777–81.

    Article  CAS  PubMed  Google Scholar 

  69. Vaux DL, Silke J. IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol. 2005;6:287–97.

    Article  CAS  PubMed  Google Scholar 

  70. Salvesen GS, Duckett CS. IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol. 2000;3:401–10.

    Article  CAS  Google Scholar 

  71. Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y. Structural and biochemical basis of apoptotic activation by SMAC/DIABLO. Nature. 2000;406:855–62.

    Article  CAS  PubMed  Google Scholar 

  72. Srinivasula SM, Hegde R, Saleh A, et al. A conserved XIAP- interaction motif in caspase-9 and SMAC/DIABLO regulates caspase activity and apoptosis. Nature. 2001;410:112–6.

    Article  CAS  PubMed  Google Scholar 

  73. Yoo NJ, Kim HS, Kim SY, et al. Immunohistochemical analysis of SMAC/DIABLO expression in human carcinomas and sarcomas. APMIS. 2003;111:382–8.

    Article  CAS  PubMed  Google Scholar 

  74. Yang QH, Church-Hajduk R, Ren J, Newton ML, Du C. Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis [IAP] irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes Dev. 2003;17:1487–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Liston P, Fong WG, Kelly NL, et al. Identification of XAF1 as an antagonist of XIAP anti-caspase activity. Nat Cell Biol. 2001;3:28–133.

    Article  CAS  Google Scholar 

  76. Ma TL, Ni PH, Zhong J, Tan JH, Qiao MM, Jiang SH. Low expression of XIAP- associated factor 1 in human colorectal cancers. Chin J Dig Dis. 2005;6:10–4.

    Article  CAS  PubMed  Google Scholar 

  77. Gross A, Mcdonnell JM, Korsmeyer SJ. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev. 1999;13:1899–911.

    Article  CAS  PubMed  Google Scholar 

  78. Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the Bcl-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014;5:49–63.

    Google Scholar 

  79. Pepper C, Bently P. The role of the Bcl-2 family in the modulation of apoptosis. Symp Soc Exp Biol. 2000;52:43–53.

    CAS  PubMed  Google Scholar 

  80. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004;305:626–9.

    Article  CAS  PubMed  Google Scholar 

  81. Frenzel A, Grespi F, Chmelewskij W, Villunger A. Bcl2 family proteins in carcinogenesis and the treatment of cancer. Apoptosis. 2009;14:584–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Camisasca DR, Honorato J, Bernardo V, et al. Expression of Bcl-2 family proteins and associated clinicopathologic factors predict survival outcome in patients with oral squamous cell carcinoma. Oral Oncol. 2009;45:225–33.

    Article  CAS  PubMed  Google Scholar 

  83. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009;15:126–1132.

    Article  CAS  Google Scholar 

  84. Lessene G, Czabotar PE, Colman PM. Bcl-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008;7:989–1000.

    Article  CAS  PubMed  Google Scholar 

  85. Hwang JJ, Kuruvilla J, Mendelson D, et al. Phase I dose finding studies of obatoclax (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced solid tumors or lymphoma. Clin Cancer Res. 2010;16:4038–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Anderson MA, Huang D, Roberts A. Targeting Bcl2 for the treatment of lymphoid malignancies. Semin Hematol. 2014;51:219–27.

    Article  CAS  PubMed  Google Scholar 

  87. Mahmood Z, Shukla Y. Death receptors: targets for cancer therapy. Exp Cell Res. 2010;316:887–99.

    Article  CAS  PubMed  Google Scholar 

  88. Bhardwaj A, Aggarwal BB. Receptor-mediated choreography of life and death. J Clin Immunol. 2003;23:317–32.

    Article  CAS  PubMed  Google Scholar 

  89. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Sciences. 1998;281:1305–8.

    Article  CAS  Google Scholar 

  90. Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2012;119:651–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Naismith JH, Sprang SR. Modularity in the TNF receptor family. Trends Biochem Sci. 1998;23:74–9.

    Article  CAS  PubMed  Google Scholar 

  92. Fulda S, Debatin KM. Exploiting death receptor signaling pathways for tumor therapy. Biochim Biophys Acta. 1705;2004:27–41.

    Google Scholar 

  93. Bremer E. Targeting of the tumor necrosis factor receptor superfamily for cancer immunotherapy. ISRN Oncol. 2013;2013:371854.

    PubMed  PubMed Central  Google Scholar 

  94. Walczak H, Krammer PH. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp Cell Res. 2000;256:58–66.

    Article  CAS  PubMed  Google Scholar 

  95. Behrmann I, Walczak H, Krammer PH. Structure of the human APO-1 gene. Eur J Immunol. 1994;24:3057–62.

    Article  CAS  PubMed  Google Scholar 

  96. Tauzin S, Debure L, Moreau JF, Legembre P. CD95-mediated cell signaling in cancer: mutations and posttranslational modulations. Cell Mol Life Sci. 2012;69:1261–77.

    Article  CAS  PubMed  Google Scholar 

  97. Scholl V, Stefanoff CG, Hassan R, Spector N, Renault IZ. Mutations within the 5′ region of FAS/CD95 gene in nodal diffuse large B-cell lymphoma. Leuk Lymphoma. 2007;48:957–63.

    Article  CAS  PubMed  Google Scholar 

  98. Ivanov VN, Ronai Z, Hei TK. Opposite roles of FAP-1 and dynamin in the regulation of Fas (CD95) translocation to the cell surface and susceptibility to Fas ligand-mediated apoptosis. J Biol Chem. 2006;281:1840–52.

    Article  CAS  PubMed  Google Scholar 

  99. Tourneur L, Mistou S, Michiels FM, et al. Loss of FADD protein expression results in a biased Fas-signaling pathway and correlates with the development of tumoral status in thyroid follicular cells. Oncogene. 2003;22:2795–280.

    Article  CAS  PubMed  Google Scholar 

  100. Fulda S, Kufer MU, Meyer E, van Valen F, Dockhorn-Dworniczak B, Debatin KM. Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene. 2001;20:5865–77.

    Article  CAS  PubMed  Google Scholar 

  101. Yang T, Shi R, Chang L, et al. Huachansu suppresses human bladder cancer cell growth through the Fas/Fasl and TNF-alpha/TNFR1 pathway in vitro and in vivo. J Exp Clin Cancer Res. 2015;34:1–10.

    Article  CAS  Google Scholar 

  102. Zhong W, Qin S, Zhu B, et al. Oxysterol-binding protein-related protein 8 [ORP8] increases sensitivity of hepatocellular carcinoma cells to Fas-mediated apoptosis. J Biol Chem. 2015;290:8876–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996;271:12687–90.

    Article  CAS  PubMed  Google Scholar 

  104. Mahalingam D, Szegezdi E, Keane M, de Jong S, Samali A. TRAIL receptor signalling and modulation: are we on the right TRAIL? Cancer Treat Rev. 2009;35:280–8.

    Article  CAS  PubMed  Google Scholar 

  105. Wu GS. TRAIL as a target in anti-cancer therapy. Cancer Lett. 2009;285:1–5.

    Article  CAS  PubMed  Google Scholar 

  106. O’Leary L, van der Sloot AM, Reis CR, et al. Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity. Oncogene. 2015. doi:10.1038/onc.2015.180.

    PubMed  Google Scholar 

  107. Woo JK, Kang JH, Jang YS, et al. Evaluation of preventive and therapeutic activity of novel non-steroidal anti-inflammatory drug, CG100649, in colon cancer: increased expression of TNF-related apoptosis-inducing ligand receptors enhance the apoptotic response to combination treatment with TRAIL. Oncol Rep. 2015;3:1947–55.

    Google Scholar 

  108. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998;273:14363–7.

    Article  CAS  PubMed  Google Scholar 

  109. Weichhaus M, Chung ST, Connelly L. Osteoprotegerin in breast cancer: beyond bone remodeling. Mol Cancer. 2015;14:117.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Lane D, Matte I, Rancourt C, Piché A. Osteoprotegerin [OPG] protects ovarian cancer cells from TRAIL-induced apoptosis but does not contribute to malignant ascites-mediated attenuation of TRAIL-induced apoptosis. J Ovarian Res. 2012;5:34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Merino D, Lalaoui N, Morizot A, Solary E, Micheau O. TRAIL in cancer therapy: present and future challenges. Expert Opin Ther Targets. 2007;11:1299–314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gong B, Almasan A. Genomic organization and transcriptional regulation of human APO2/TRAIL gene. Biochem Biophys Res Commun. 2000;278:747–52.

    Article  CAS  PubMed  Google Scholar 

  113. Krieg A, Krieg T, Wenzel M, et al. TRAIL-beta and TRAIL-gamma: two novel splice variants of the human TNF-related apoptosis- inducing ligand (TRAIL) without apoptotic potential. Br J Cancer. 2003;88:918–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Pal R, Gochhait S, Chattopadhyay S, et al. Functional implication of TRAIL-716 C/T promoter polymorphism on its in vitro and in vivo expression and the susceptibility to sporadic breast tumor. Breast Cancer Res Treat. 2012;126:333–43.

    Article  Google Scholar 

  115. Bos PD, Zhang XHF, Nadal C, et al. Genes that mediate breast cancer metastasis to the brain. Nature. 2009;459:1005–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Allen JE, El-Deiry WS. Regulation of the human TRAIL gene. Cancer Biol Ther. 2012;13:1143–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lim B, Allen JE, Prabhu VV, Talekar MK, Finnberg NK, El-Deiry WS. Targeting TRAIL in the treatment of cancer: new developments. Expert Opin Ther Targets. 2015;25:1–15.

    Article  CAS  Google Scholar 

  118. Falvo JV, Tsytsykova AV, Goldfeld AE. Transcriptional control of the TNF gene. Curr Dir Autoimmun. 2010;11:27–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10:45–65.

    Article  CAS  PubMed  Google Scholar 

  120. Sedger LM, McDermott MF. TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants—past, present and future. Cytokine Growth Factor Rev. 2014;25:453–72.

    Article  CAS  PubMed  Google Scholar 

  121. Wachter T, Sprick M, Hausmann D, et al. cFLIPL inhibits tumor necrosis factor-related apoptosis-inducing ligand-mediated NF-kappaB activation at the death-inducing signaling complex in human keratinocytes. J Biol Chem. 2004;279:52824–34.

    Article  CAS  PubMed  Google Scholar 

  122. Ebach DR, Riehl TE, Stenson WF. Opposing effects of tumor necrosis factor receptor 1 and 2 in sepsis due to cecal ligation and puncture. Shock. 2005;23:311–8.

    Article  CAS  PubMed  Google Scholar 

  123. Yun HM, Park KR, Kim EC, Han SB, Yoon do Y, Hong JT. IL-32α suppresses colorectal cancer development via TNFR1-mediated death signaling. Oncotarget. 2015;6:9061–72.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Yu S, Hou D, Chen P, et al. Adenosine induces apoptosis through TNFR1/RIPK1/P38 axis in colon cancer cells. Biochem Biophys Res Commun. 2015;460:759–65.

    Article  CAS  PubMed  Google Scholar 

  125. Bake V, Roesler S, Eckhardt I, Belz K, Fulda S. Synergistic interaction of SMAC mimetic and IFNα to trigger apoptosis in acute myeloid leukemia cells. Cancer Lett. 2014;355:224–31.

    Article  CAS  PubMed  Google Scholar 

  126. Tao YF, Lu J, Du XJ, et al. Survivin selective inhibitor YM155 induce apoptosis in SK-NEP-1 Wilms tumor cells. BMC Cancer. 2012;26(12):619.

    Article  CAS  Google Scholar 

  127. Ruddle NH. Lymphotoxin and TNF: how it all began—a tribute to the travelers. Cytokine Growth Factor Rev. 2014;25:83–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Chaturvedi MM, LaPushin R, Aggarwal BB. Tumor necrosis factor and lymphotoxin. Qualitative and quantitative differences in the mediation of early and late cellular response. J Biol Chem. 1994;269:14575–83.

    CAS  PubMed  Google Scholar 

  129. Etemadi N, Holien JK, Chau D, et al. Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor. FEBS J. 2013;280:5283–97.

    Article  CAS  PubMed  Google Scholar 

  130. de Oliveira JG, Rossi AF, Nizato DM, et al. Influence of functional polymorphisms in TNF-α, IL-8, and IL-10 cytokine genes on mRNA expression levels and risk of gastric cancer. Tumour Biol. 2015 (Epub ahead of print).

  131. Kang YJ, Kim WJ, Bae HU, et al. Involvement of TL1A and DR3 in induction of proinflammatory cytokines and matrix metalloproteinase-9 in atherogenesis. Cytokine. 2005;29:229–35.

    Article  CAS  PubMed  Google Scholar 

  132. Lee SY, Debnath T, Kim SK, Lim BO. Anti-cancer effect and apoptosis induction of cordycepin through DR3 pathway in the human colonic cancer cell HT-29. Food Chem Toxicol. 2013;60:439–47.

    Article  CAS  PubMed  Google Scholar 

  133. Oh SB, Hwang CJ, Song SY, et al. Anti-cancer effect of tectochrysin in NSCLC cells through overexpression of death receptor and inactivation of STAT3. Cancer Lett. 2014;353:95–103.

    Article  CAS  PubMed  Google Scholar 

  134. Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9:749–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Surget S, Khoury MP, Bourdon J. Uncovering the role of p53 splice variants in human malignancy: a clinical perspective. Onco Targets Ther. 2013;7:57–68.

    PubMed  PubMed Central  Google Scholar 

  136. Mollereau B, Ma D. The p53 control of apoptosis and proliferation: lessons from Drosophila. Apoptosis. 2014;19:1421–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Pflaum J, Schlosser S, Müller M. p53 family and cellular stress responses in cancer. Front Oncol. 2014;4:285.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Beckerman R, Prives C. Transcriptional regulation by p53. Cold Spring Harb Perspect Biol. 2010;2:a000935.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Chi SW. Structural insights into the transcription-independent apoptotic pathway of p53. BMB Rep. 2014;47:167–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis—the p53 network. J Cell Sci. 2003;116:4077–85.

    Article  CAS  PubMed  Google Scholar 

  141. Perry ME. The regulation of the p53-mediated stress response by MDM2 and MDM4. Cold Spring Harb Perspect Biol. 2010;2:a000968.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Riley MF, You MJ, Multani AS, Lozano G. Mdm2 overexpression and p73 loss exacerbate genomic instability and dampen apoptosis, resulting in B-cell lymphoma. Oncogene. 2015. doi:10.1038/onc.2015.88(Epubaheadofprint).

    PubMed  PubMed Central  Google Scholar 

  143. Jansson MD, Damas ND, Lees M, Jacobsen A, Lund AH. miR-339-5p regulates the p53 tumor-suppressor pathway by targeting MDM2. Oncogene. 2014;34:1908–18.

    Article  PubMed  CAS  Google Scholar 

  144. Yu J, Zhang L. PUMA, a potent killer with or without p53. Oncogene Suppl. 1998;1:S71–83.

    Google Scholar 

  145. Hikisz P, Kiliańska ZM. PUMA, a critical mediator of cell death—one decade on from its discovery. Cell Mol Biol Lett. 2012;17:646–69.

    Article  CAS  PubMed  Google Scholar 

  146. Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem. 2002;277:3247–57.

    Article  CAS  PubMed  Google Scholar 

  147. MacLachlan TK, El-Deiry WS. Apoptotic threshold is lowered by p53 transactivation of caspase-6. Proc Natl Acad Sci U S A. 2002;99:9492–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Mihara M, Erster S, Zaika A, et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003;11:577–90.

    Article  CAS  PubMed  Google Scholar 

  149. Ha JH, Shin JS, Yoon MK, et al. Dual-site interactions of p53 protein transactivation domain with anti-apoptotic Bcl-2 family proteins reveal a highly convergent mechanism of divergent p53 pathways. J Biol Chem. 2013;288:7387–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Chipuk JE, Kuwana T, Bouchier-Hayes L, et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 2004;303:1010–4.

    Article  CAS  PubMed  Google Scholar 

  151. Leu JI, Dumont P, Hafey M, Murphy ME, George DL. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1complex. Nat Cell Biol. 2004;6:443–50.

    Article  CAS  PubMed  Google Scholar 

  152. Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinicaluse. Cold Spring Harb Perspect Biol. 2010;2:a001008.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 2009;9:701–13.

    CAS  PubMed  Google Scholar 

  154. Saleem S, Abbasi ZA, Hameed A, Qureshi NR, Khan MA, Azhar A. Novel p53 codon 240 Ser > Thr coding region mutation in the patients of oral squamous cell carcinoma (OSCC). Tumour Biol. 2014;35:7945–50.

    Article  CAS  PubMed  Google Scholar 

  155. Trbusek M, Smardova J, Malcikova J, et al. Missense mutations located in structural p53 DNA-binding motifs are associated with extremely poor survival in chronic lymphocytic leukemia. J Clin Oncol. 2011;29:2703–8.

    Article  CAS  PubMed  Google Scholar 

  156. Wang S, Zhou M, Ouyang J, Geng Z, Wang Z. Tetraarsenictetrasulfide and arsenic trioxide exert synergistic effects on induction of apoptosis and differentiation in acute promyelocytic leukemia cells. PLoS One. 2015;10:e0130343.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Gu ZT, Li L, Wu F, et al. Heat stress induced apoptosis is triggered by transcription-independent p53, Ca[2+] dyshomeostasis and the subsequent Bax mitochondrial translocation. Sci Rep. 2015;5:11497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Sosin AM, Burger AM, Siddiqi A, Abrams J, Mohammad RM, Al-Katib AM. HDM2 antagonist MI-219 [spiro-oxindole], but not Nutlin-3 [cis-imidazoline], regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas. J Hematol Oncol. 2012;5:57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Boeckler FM, Joerger AC, Jaggi G, Rutherford TJ, Veprintsev DB, Fersht AR. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci U S A. 2008;105:10360–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Vermeij R, Leffers N, van der Burg SH, Melief CJ, Daemen T, Nijman HW. Immunological and clinical effects of vaccines targeting p53-overexpressing malignancies. J Biomed Biotechnol. 2011;2011:702146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Lima RT, Busacca S, Almeida GM, Gaudino G, Fennell DA, Vasconcelos MH. MicroRNA regulation of core apoptosis pathways in cancer. Eur J Cancer. 2011;47:163–74.

    Article  CAS  PubMed  Google Scholar 

  162. Chen Y, Fu LL, Wen X, et al. Oncogenic and tumor suppressive roles of microRNAs in apoptosis and autophagy. Apoptosis. 2014;19:1177–89.

    Article  CAS  PubMed  Google Scholar 

  163. Acunzo M, Visone R, Romano G, et al. Mir-130a targets MET and induces trail-sensitivity in NSCLC by downregulating mir-221 and 222. Oncogene. 2012;31:634–42.

    CAS  PubMed  Google Scholar 

  164. Hao J, Zhang C, Zhang A, et al. miR-221/222 is the regulator of Cx43 expression in human glioblastoma cells. Oncol Rep. 2012;27:1504–10.

    CAS  PubMed  Google Scholar 

  165. Wang P, Zhuang L, Zhang J, et al. The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Mol Oncol. 2013;7:334–45.

    Article  CAS  PubMed  Google Scholar 

  166. Qin W, Shi Y, Zhao B, et al. miR-24 regulates apoptosis by targeting the open reading frame (ORF) region of FAF1 in cancer cells. PLoS ONE. 2010;5:e9429.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Satzger I, Mattern A, Kuettler U, et al. microRNA-21 is upregulated in malignant melanoma and influences apoptosis of melanocytic cells. Exp Dermatol. 2012;21:509–14.

    Article  CAS  PubMed  Google Scholar 

  168. Eto K, Iwatsuki M, Watanabe M, et al. The microRNA-21/PTEN pathway regulates the sensitivity of HER2-positive gastric cancer cells to trastuzumab. Ann Surg Oncol. 2013;21:343–50.

    Article  PubMed  Google Scholar 

  169. Schickel R, Park SM, Murmann AE, Peter ME. miR-200c regulates induction of apoptosis through CD95 by targeting FAP-1. Mol Cell. 2010;38:908–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Li JH, Xiao X, Zhang YN, et al. MicroRNA miR-886-5p inhibits apoptosis by down-regulating Bax expression in human cervical carcinoma cells. Gynecol Oncol. 2011;120:145–51.

    Article  CAS  PubMed  Google Scholar 

  171. Zhou M, Liu Z, Zhao Y, et al. MicroRNA-125b confers the resistance of breast cancer cells to paclitaxel through suppression of pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) expression. J Biol Chem. 2010;285:21496–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Zhang H, Zuo Z, Lu X, Wang L, Wang H, Zhu Z. MiR-25 regulates apoptosis by targeting Bim in human ovarian cancer. Oncol Rep. 2012;27:594–8.

    CAS  PubMed  Google Scholar 

  173. Gocek E, Wang X, Liu X, Liu CG, Studzinski GP. MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis. Cancer Res. 2011;71:6230–9.

    Article  CAS  PubMed  Google Scholar 

  174. Veronese A, Lupini L, Consiglio J, et al. Oncogenic role of miR-483-3p at the IGF2/483 locus. Cancer Res. 2010;70:3140–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Tanaka N, Toyooka S, Soh J, et al. Downregulation of microRNA-34 induces cell proliferation and invasion of human mesothelial cells. Oncol Rep. 2013;29:2169–74.

    PubMed  Google Scholar 

  176. Shen J, Wan R, Hu G, et al. miR-15b and miR-16 induce the apoptosis of rat activated pancreatic stellate cells by targeting Bcl-2 in vitro. Pancreatology. 2012;12:91–9.

    Article  CAS  PubMed  Google Scholar 

  177. Xu J, Liao X, Wong C. Downregulations of B-cell lymphoma 2 and myeloid cell leukemia sequence 1 by microRNA 153 induce apoptosis in a glioblastoma cell line DBTRG-05MG. Int J Cancer. 2010;126:1029–35.

    CAS  PubMed  Google Scholar 

  178. Nakano H, Miyazawa T, Kinoshita K, Yamada Y, Yoshida T. Functional screening identifies a microRNA, miR-491 that induces apoptosis by targeting Bcl-X(L) in colorectal cancer cells. Int J Cancer. 2010;127:1072–80.

    Article  CAS  PubMed  Google Scholar 

  179. Shang J, Yang F, Wang Y, et al. Sun S MicroRNA-23a antisense enhances 5-fluorouracil chemosensitivity through APAF-1/caspase-9 apoptotic pathway in colorectal cancer cells. J Cell Biochem. 2014;115:772–84.

    Article  CAS  PubMed  Google Scholar 

  180. Walker JC, Harland RM. MicroRNA-24a is required to repress apoptosis in the developing neural retina. Genes Dev. 2009;23:1046–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Wu JH, Yao YL, Gu T, et al. MiR-421 regulates apoptosis of BGC-823 gastric cancer cells by targeting caspase-3. Asian Pac J Cancer Prev. 2014;15:5463–8.

    Article  PubMed  Google Scholar 

  182. Hudson RS, Yi M, Esposito D, et al. Microrna-106b-25 cluster expression is associated with early disease recurrence and targets caspase-7 and focal adhesion in human prostate cancer. Oncogene. 2013;32:4139–47.

    Article  CAS  PubMed  Google Scholar 

  183. Floyd DH, Zhang Y, Dey BK, et al. Novel anti-apoptotic microRNAs 582–5p and 363 promote human glioblastoma stem cell survival via direct inhibition of caspase 3, caspase 9, and Bim. PLoS One. 2014;9:e96239.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Tsang WP, Kwok TT. Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3. Apoptosis. 2008;13:1215–22.

    Article  CAS  PubMed  Google Scholar 

  185. Zhang J, Du Y, Wu C, et al. Curcumin promotes apoptosis in human lung adenocarcinoma cells through miR-186 signaling pathway. Oncol Rep. 2010;24:1217–23.

    CAS  PubMed  Google Scholar 

  186. Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008;9:139–50.

    Article  CAS  PubMed  Google Scholar 

  187. Barth BM, Cabot MC, Kester M. Ceramide-based therapeutics for the treatment of cancer. Anti Cancer Agents Med Chem. 2011;11:911–9.

    Article  CAS  Google Scholar 

  188. Senchenkov A, Litvak DA, Cabot MC. Targeting ceramide metabolism—a strategy for overcoming drug resistance. J Natl Cancer Inst. 2001;93:347–57.

    Article  CAS  PubMed  Google Scholar 

  189. Siskind LJ, Kolesnick RN, Colombini M. Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. J Biol Chem. 2002;277:26796–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Siskind LJ, Feinstein L, Yu TX, et al. Anti-apoptotic Bcl-2 family proteins disassemble ceramide channels. J Biol Chem. 2008;283:6622–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. von Haefen C, Wieder T, Gillissen B, et al. Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene. 2002;21:4009–19.

    Article  CAS  Google Scholar 

  192. Dumitru CA, Sandalcioglu IE, Wagner M, Weller M, Gulbins E. Lysosomal ceramide mediates gemcitabine-induced death of glioma cells. J Mol Med. 2009;87:1123–32.

    Article  CAS  PubMed  Google Scholar 

  193. Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer: pathogenesis and treatment. Nat Rev Cancer. 2004;4:604–16.

    Article  CAS  PubMed  Google Scholar 

  194. Liu F, Verin AD, Wang P, et al. Differential regulation of sphingosine-1-phosphate- and VEGF-induced endothelial cell chemotaxis. Involvement of G(ialpha2)-linked Rho kinase activity. Am J Respir Cell Mol Biol. 2001;24:711–9.

    Article  CAS  PubMed  Google Scholar 

  195. Radin NS. The development of aggressive cancer: a possible role for sphingolipids. Cancer Investig. 2002;20:779–86.

    Article  Google Scholar 

  196. Pchejetski D, Golzio M, Bonhoure E, et al. Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models. Cancer Res. 2005;65:11667–75.

    Article  CAS  PubMed  Google Scholar 

  197. Beckham TH, Lu P, Jones EE, et al. LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria. J Pharmacol Exp Ther. 2013;344(1):167–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Jiang Y, DiVittore NA, Kaiser JM, et al. Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. Cancer Biol Ther. 2011;12(7):574–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Sorli SC, Colié S, Albinet V, et al. The nonlysosomal β-glucosidase GBA2 promotes endoplasmic reticulum stress and impairs tumorigenicity of human melanoma cells. FASEB J. 2013;27(2):489–98.

    Article  CAS  PubMed  Google Scholar 

  200. Stover TC, Sharma A, Robertson GP, Kester M. Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin Cancer Res. 2005;11(9):3465–74.

    Article  CAS  PubMed  Google Scholar 

  201. Beljanski V, Lewis CS, Smith CD. Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts. Cancer Biol Ther. 2011;11(5):524–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Adan-Gokbulut A, Kartal-Yandim M, Iskender G, Baran Y. Novel agents targeting bioactive sphingolipids for the treatment of cancer. Curr Med Chem. 2013;20(1):108–22.

    Article  CAS  PubMed  Google Scholar 

  203. Coward J, Ambrosini G, Musi E, Truman JP, Haimovitz-Friedman A, Allegood JC. Safingol (L-threo-sphinganine) induces autophagy in solid tumor cells through inhibition of PKC and the PI3-kinase pathway. Autophagy. 2009;5:184–93.

    Article  CAS  PubMed  Google Scholar 

  204. Pyne S, Bittman R, Pyne NJ. Sphingosine kinase inhibitors and cancer: seeking the golden sword of Hercules. Cancer Res. 2011;71(21):6576–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Taouji S, Higa A, Delom F, et al. Phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on tyrosine 164 inhibits its activity and promotes cell survival. J Biol Chem. 2013;288(24):17190–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Huang WC, Tsai CC, Chen CL, et al. Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis. FASEB J. 2011;25(10):3661–73.

    Article  CAS  PubMed  Google Scholar 

  207. Nica AF, Tsao CC, Watt JC, et al. Ceramide promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving caspase-8 and JNK. Cell Cycle. 2008;7(21):3362–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Camgoz A, Gencer EB, Ural AU, Baran Y. Mechanisms responsible for nilotinib resistance in human chronic myeloid leukemia cells and reversal of resistance. Leukemia Lymphoma. 2013;54:1279–87.

    Article  CAS  PubMed  Google Scholar 

  209. Baran Y, Bielawski J, Gunduz U, Ogretmen B. Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation. J Cancer Res Clin Oncol. 2011;137:1535–44.

    Article  CAS  PubMed  Google Scholar 

  210. Kartal M, Saydam G, Sahin F, Baran Y. Resveratrol triggers apoptosis through regulating ceramide metabolizing genes in human K562 chronic myeloid leukemia cells. Nutr Cancer. 2011;63(4):637–44.

    Article  CAS  PubMed  Google Scholar 

  211. Cakir Z, Saydam G, Sahin F, Baran Y. The roles of bioactive sphingolipids in resveratrol-induced apoptosis in HL60: acute myeloid leukemia cells. J Cancer Res Clin Oncol. 2011;137(2):279–86.

    Article  CAS  PubMed  Google Scholar 

  212. Camgoz A, Gencer EB, Ural AU, Avcu F, Baran Y. Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloid leukemia cells. Leukemia Lymphoma. 2011;52:1574–84.

    Article  CAS  PubMed  Google Scholar 

  213. Gencer EB, Ural AU, Avcu F, Baran Y. A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes. Ann Hematol. 2011;90:1265–75.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yusuf Baran.

Ethics declarations

Conflict of interest

None

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kiraz, Y., Adan, A., Kartal Yandim, M. et al. Major apoptotic mechanisms and genes involved in apoptosis. Tumor Biol. 37, 8471–8486 (2016). https://doi.org/10.1007/s13277-016-5035-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5035-9

Keywords

Navigation