Pathology Oncology Research

, Volume 7, Issue 2, pp 95–106 | Cite as

Shared pathways: Death receptors and cytotoxic drugs in cancer therapy



Death ligands (TNF, FasL, TRAIL) and their respective death receptor signaling pathways can be used to induce tumor cells to undergo apoptosis. Chemotherapeutic drugs can induce apoptosis and the upregulation of death ligands or their receptors. Downstream events following cytotoxic stressinduced DNA damage and the signaling pathways that lead to the induction of apoptosis may be either dependent or independent of death receptor signaling. The involvement of the Fas signaling pathway in chemotherapy-induced apoptosis has been the most extensively studied, with the current emergence of information on the TRAIL signaling pathway. Fas-mediated and chemotherapy-induced apoptosis can converge at the level of the receptor, FasL, DISC formation, activation of the initiator caspase-8, at the level of the mitochondria, or at the level of downstream effector caspase activation. Convergence is influenced by the specific form of DNA damage, the cellular environment, and the specific pathway(s) by which death receptor-mediated or drug-mediated apoptosis are induced. This review discusses the different levels of interaction between signaling pathways in the different forms of cell death.


apoptosis tumor death receptor Fas drug p53 


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  1. 1.2
    Ashkenazi A, Dixit VM: Death receptors: Signaling and modulation. Science 281:305–108, 1998.CrossRefGoogle Scholar
  2. 2.2
    Ware CF, VanArsdale S, VanArsdale TL: Apoptosis mediated by the TNF-related cytokine and receptor families. J Cell Biochem 60:47–55, 1996.PubMedCrossRefGoogle Scholar
  3. 3.2
    McGeehan GM, Becherer JD, Bast RCJr, et al: Regulation of tumor necrosis factor-alpha processing by a metalloproteinase inhibitor. Nature 370:558–561, 1994.PubMedCrossRefGoogle Scholar
  4. 4.2
    Tanaka M, Itai T, Adachi M, et al: Downregulation of Fas ligand by shedding. Nature Med 4:31–36, 1998.PubMedCrossRefGoogle Scholar
  5. 5.2
    Kayagaki N, Kawasaki A, Ebata T, et al: Metalloproteinasemediated release of human Fas ligand. J Exp Med 182:1777–1783, 1995.PubMedCrossRefGoogle Scholar
  6. 6.2
    Ashkenazi A, Dixit VM: Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 11:255–260, 1999.PubMedCrossRefGoogle Scholar
  7. 7.2
    Nagata S, Golstein P:The Fas death factor. Science 276:1449, 1995.CrossRefGoogle Scholar
  8. 8.2
    Aral H, Gordon D, Nabel EG, et al: Gene transfer of Fas ligand induces tumor regression in vivo. Proc Natl Acad Sci USA 94:13862–13867, 1997.CrossRefGoogle Scholar
  9. 9.2
    French LE, Hahne M, Viard I, et al: Fas and Fas ligand in embryos and adult mice: ligand expression in several immuneprivileged tissues and coexpression in adult tissues characterized by apoptotic cell turnover. J Cell Biol 133:335–343, 1996.PubMedCrossRefGoogle Scholar
  10. 10.2
    Moller P, Koretz K, Leithauser F, et al: Expression of Apo-1 (CD95), a member of the NGF/TNF receptor superfamily, in normal and neoplastic colon epithelium. Int J Cancer 57:371–377, 1994.PubMedCrossRefGoogle Scholar
  11. 11.2
    Pitti RM, Marsters SA, Lawrence DA, et al: Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature. 396:699–703. 1998.PubMedCrossRefGoogle Scholar
  12. 12.2
    Itoh N, Yonehara S, Ishii A Itoh N, Yonehara S, Ishii A, et al: The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66:233–243, 1991.PubMedCrossRefGoogle Scholar
  13. 13.2
    Boldin MP, Varfolomeev EE, Pancer Z, et al: A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem 270:7795–7798, 1995.PubMedCrossRefGoogle Scholar
  14. 14.2
    Chinnaiyan AM, O’Rourke K, Tewari M, et al: FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81:505–512, 1995.PubMedCrossRefGoogle Scholar
  15. 15.2
    Boldin MP, Goncharov TM, Goltsev YV, et al: Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO1 and TNF receptor-induced cell death. Cell 85:803–815, 1996.PubMedCrossRefGoogle Scholar
  16. 16.2
    Medema JP, Scaffidi C, Kischkel FC, et al: FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 16:2794–2804, 1997.PubMedCrossRefGoogle Scholar
  17. 17.2
    Muzio M, Chinnaiyan AM, Kischkel FC, et al: FLICE a novel FADD-homologous ICE/CED-3-like protease is recruited to the CD95 (Fas/Apo-1) death-inducing signaling complex. Cell 85:817–827, 1996.PubMedCrossRefGoogle Scholar
  18. 18.2
    Irmler M, Thome M, Hahne M, et al: Inhibition of death receptor signals by cellular FLIP. Nature 388:190–195. 1997.PubMedCrossRefGoogle Scholar
  19. 19.2
    Scaffidi C, Schmitz I, Krammer PH, et al: The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 274:1541–1548. 1999.PubMedCrossRefGoogle Scholar
  20. 20.2
    Scaffidi C, Fulda S, Srinivasan A, et al: Two CD95 (APO1/Fas) signaling pathways. EMBO J 17:1675–1687, 1998.PubMedCrossRefGoogle Scholar
  21. 21.2
    Sun X-M, MacFarlane M, Zhuang J, et al: Distinct caspase cascades are initiated in receptor-mediated and chemicalinduced apoptosis. J Biol Chem 274:5053–5060, 1999.PubMedCrossRefGoogle Scholar
  22. 22.2
    Kuwana T, Smith JJ, Muzio M, et al: Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c. J Biol Chem. 27:16589–16594, 1998.CrossRefGoogle Scholar
  23. 23.2
    Li P, Nijhawan D, Alnemri ES, Wang X: Cytochrome c and dATP-dependent formation of Apaf-l/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489, 1997.PubMedCrossRefGoogle Scholar
  24. 24.2
    Jeremias I, Herr I, Boehler T, et al: TRAIL/Apo-2-ligandinduced apoptosis in human T cells. Eur J Immunol 28:143–152, 1998.PubMedCrossRefGoogle Scholar
  25. 25.2
    Marsters SA, Pitti RM, Donahue CJ, et al: Activation of apoptosis by Apo-2 ligand is independent of FADD but blocked by CrmA. Curr Biol 6:750–752, 1996.PubMedCrossRefGoogle Scholar
  26. 26.2
    Griffith TS, Lynch DH: TRAIL: a molecule with multiple receptors and control mechanisms. Curr Opin Immunol 10:559–563, 1998.PubMedCrossRefGoogle Scholar
  27. 27.2
    Zhang XD, Franco AV, Nguyen T, et al: Differential Localization and Regulation of Death and Decoy Receptors for TNF-Related Apoptosis-Inducing Ligand (TRAIL) in Human Melanoma Cells. J Immunol 164:3961–3970, 2000.PubMedGoogle Scholar
  28. 28.2
    Walczak H, Miller RE, Ariail K, et al: Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nature Med 5:157–163, 1999.PubMedCrossRefGoogle Scholar
  29. 29.2
    Walczak H, Degli-Eposti MA, Johnson RS, et al: TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J 16:5386–5397, 1997.PubMedCrossRefGoogle Scholar
  30. 30.2
    Wiley SR, Schooley K, Smolak PJ, et al: Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3:673–682, 1995.PubMedCrossRefGoogle Scholar
  31. 31.2
    Pan G, O’Rourke K, Chinnaiyan AM, et al: The receptor for the cytotoxic ligand TRAIL. Science 276:111–113, 1997.PubMedCrossRefGoogle Scholar
  32. 32.2
    Pan G, Ni J, Wei Y-F, et al: An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277:815–818, 1997.PubMedCrossRefGoogle Scholar
  33. 33.2
    Sheridan JP, Marsters SA, Pitti PM, et al: Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277:818–821, 1997.PubMedCrossRefGoogle Scholar
  34. 34.2
    Degli-Eposti MA, Smolak PJ, Walczak H, et al: Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J Exp Med 186:1165–1170, 1997.CrossRefGoogle Scholar
  35. 35.2
    Degli-Eposti MA, Dougall WC, Smolak PJ, et al: The novel receptor TRAIL-R4 induces NF-kB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 7:813–820, 1997.CrossRefGoogle Scholar
  36. 36.2
    Marsters SA, Sheridan JP, Pitti RM, et al: A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol 7:1003–1006, 1997.PubMedCrossRefGoogle Scholar
  37. 37.2
    Frank S, Kohler U, Schackert G, et al: Expression of TRAIL and its receptors in human brain tumors. Biochem Biophys Res Commun 257:454–459, 1999.PubMedCrossRefGoogle Scholar
  38. 38.2
    Griffith TS, Chin WA, Jackson GC, et al: Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol 161:2833–2840, 1998.PubMedGoogle Scholar
  39. 39.2
    Thomas WD, Hersey P: TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells. J Immunol 161:2195–2200, 1998.PubMedGoogle Scholar
  40. 40.2
    Ashkenazi A, Pai RC, Fong S, et al: Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 104:155–162, 1999.PubMedCrossRefGoogle Scholar
  41. 41.2
    Rieger J, Naumann U, Glaser T, et al: APO2 ligand: a novel weapon against malignant glioma? FEBS Lett 427:124–128, 1998.PubMedCrossRefGoogle Scholar
  42. 42.2
    Schneider P, Thome M, Burns K, et al: TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 7:831–6, 1997.PubMedCrossRefGoogle Scholar
  43. 42.2
    Schneider P, Thome T, Burns K, et al: TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 7:831–836, 1997.PubMedCrossRefGoogle Scholar
  44. 43.2
    Kischkel FC, Lawrence DA, Chuntharapai A, et al: Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12:611–620, 2000.PubMedCrossRefGoogle Scholar
  45. 44.2
    Sprick MR, Weigand MA, Rieser E, et al: FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12:599–609, 2000.PubMedCrossRefGoogle Scholar
  46. 45.2
    Bodmer JL, Holler N, Reynard S, et al: TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol 2:241–243, 2000.PubMedCrossRefGoogle Scholar
  47. 46.2
    Hickman JA: Apoptosis induced by anticancer drugs. Cancer Metast Rev 11:121–139, 1992.CrossRefGoogle Scholar
  48. 47.2
    Holzman D: Apoptosis provides new targets for chemotherapy. J Natl Cancer Inst 88:1098–1100, 1996.PubMedCrossRefGoogle Scholar
  49. 48.2
    Sellers WR, Fisher DE: Apoptosis and cancer drug targeting. J Clin Invest 104:1655–1661, 1999.PubMedCrossRefGoogle Scholar
  50. 49.2
    Miyashita T, Reed JC: Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81:151–157, 1993.PubMedGoogle Scholar
  51. 50.2
    Bunz F, Hwang PM, Torrance C, et al: Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J Clin Invest 104:263–269, 1999.PubMedCrossRefGoogle Scholar
  52. 51.2
    Zhu H, Fearnhead HO, Cohen GM: An ICE-like protease is a common mediator of apoptosis induced by diverse stimuli in human monocytic THP.l cells. FEBS LETT 375:303–308, 1995.CrossRefGoogle Scholar
  53. 52.2
    Petak I, Mihalik R, Bauer PI, et al: BCNU is a caspase-mediated inhibitor of drug-induced apoptosis. Cancer Res 58:614–618, 1998.PubMedGoogle Scholar
  54. 53.2
    Petak I, Tillman, DM, Harwood FG, et al: Fas-dependent and -independent mechanisms of cell death following DNA damage in human colon carcinoma cells. Cancer Res 60:2643–2650. 2000.PubMedGoogle Scholar
  55. 54.2
    Tounekti O, Pron G, Belehradek J, et al: Bleomycin, an apoptosis-mimetic drug that induces two types of cell death depending on the number of molecules internalized. Cancer Res 53:5462–5469, 1993.PubMedGoogle Scholar
  56. 55.2
    Skladanowski A, Konopa, J: Adriamycin and daunomycin induce programmed cell death (apoptosis) in tumour cells. Biochem Pharmacol 46:375–382, 1993.PubMedCrossRefGoogle Scholar
  57. 56.2
    Pellicciari C, Bottone MG, Schaack V, et al: Etoposide at different concentrations may open different apoptotic pathways in thymocytes. Eur J Histochem 40:289–298, 1996.PubMedGoogle Scholar
  58. 57.2
    Lock RB, Stribinskiene L: Dual modes of death induced by etoposide in human epithelial tumor cells allow Bcl-2 to inhibit apoptosis without affecting clonogenic survival. Cancer Res 56:4006–4012, 1996.PubMedGoogle Scholar
  59. 58.2
    Kasibhatla S, Brunner T, Genestier L, et al: DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol Cell 1, 543–551. 1998.PubMedCrossRefGoogle Scholar
  60. 59.2
    Faris M, Kokot N, Latinis K, et al: The c-Jun N-terminal kinase cascade plays a role in stress-induced apoptosis in Jurkat cells by up-regulating Fas ligand expression. J Immunol 160:134–144, 1998.PubMedGoogle Scholar
  61. 60.2
    Friesen C, Herr I, Krammer PH, et al: Involvement of the CD95 (APO-1/Fas) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nature Med 2:574–577, 1996.PubMedCrossRefGoogle Scholar
  62. 61.2
    Fulda S, Sievens H, Frieson C, et al: The CD95 (APO l-Fas) system mediates drug-induced apoptosis in neuroblastoma cells. Cancer Res 57:3823–3829, 1997.PubMedGoogle Scholar
  63. 62.2
    Villunger A, Egle A, Kos M, et al: Drug-induced apoptosis is associated with enhanced Fas (APO-1/CD9J) ligand expression but occurs independently of Fas (APO-1/CD95) signaling in human T-acute lymphatic leukemia cells. Cancer Res 57:3331–3334, 1997PubMedGoogle Scholar
  64. 63.2
    Eischen CM, Kottke TJ, Martins LM, et al: Comparison of Apoptosis in wild-type and Fas-resistant cells: chemotherapyinduced apoptosis is not demendent on Fas/Fas ligand interactions. Blood 90:935–943, 1997.PubMedGoogle Scholar
  65. 64.2
    Wen J, Ramadevi N, Nguyen D, et al: Antileukemic drugs increase death receptor 5 levels and enhance apo-2L-induced apoptosis of human acute leukemia cells. Blood 96:3900–3906, 2000.PubMedGoogle Scholar
  66. 65.2
    Nagane M, Pan G, Weddle JJ, et al: Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factorrelated apoptosis-inducing ligand in vitro and in vivo. Cancer Res 60:847–853, 2000.PubMedGoogle Scholar
  67. 66.2
    Keane MM, Ettenberg SA, Nau MM, et al: Chemotherapy augmants TRAIL-induced apoptosis in breast cell lines. Cancer Res 59:734–741, 1999.PubMedGoogle Scholar
  68. 67.2
    Alderson MR, Tough TW Davissmith T, et al: Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med 181:71–77, 1995.PubMedCrossRefGoogle Scholar
  69. 68.2
    Brunner T, Mogil RJ, La Face D, et al: Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373:441–444, 1995.PubMedCrossRefGoogle Scholar
  70. 69.2
    Fulda S, Strauss G, Meyer E, et al: Functional CD95 ligand and CD95 death-inducing signaling complex in activation-induced cell death and doxorubicin-induced apoptosis in leukemic T cells. Blood 95:301–308, 2000.PubMedGoogle Scholar
  71. 70.2
    Fulda S, Meyer E, Friesen C, et al: Cell type specific involvement of death receptor and mitochondrial pathways in druginduced apoptosis. Oncogene 20:1063–1075, 2001.PubMedCrossRefGoogle Scholar
  72. 71.2
    Houghton JA, Harwood FG, Tillman DM: Thymineless death in colon carcinoma cells is mediated via Fas signaling. Proc Natl Acad Sci USA 94:8144–8149, 1997.PubMedCrossRefGoogle Scholar
  73. 72.2
    Tillman DM, Petak I, Houghton JA: A Fas-dependent component in 5-fluorouracil/leucovorin-induced cytotoxicity in colon carcinoma cells. Clin Cancer Res 5:425–430. 1999.PubMedGoogle Scholar
  74. 73.2
    Eichhorst ST, Muller M, Li-Weber M, et al: A novel AP-1 element in the CD95 ligand promoter is required for induction of apoptosis in hepatocellular carcinoma cells upon treatment with anticancer drugs. Mol Cell Biol 20:7826–7837, 2000.PubMedCrossRefGoogle Scholar
  75. 74.2
    Eichhorst ST, Muerkoster S, Weigand MA, et al: The chemotherapeutic drug 5-fluorouracil induces apoptosis in mouse thymocytes in vivo via activation of the CD95(APO-1/Fas) system. Cancer Res 61:243–248. 2001.PubMedGoogle Scholar
  76. 75.2
    Harwood FG, Kasibhatla S, Petak I, et al: Regulation of FasL by NF-kappaB and AP-1 in Fas-dependent thymineless death of human colon carcinoma cells. J Biol Chem 275:10023–10029. 2000.PubMedCrossRefGoogle Scholar
  77. 76.2
    Muller M, Wilder S, Bannasch D, et al: P53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer agents. J Exp Med., 188:2033–2045, 1998.PubMedCrossRefGoogle Scholar
  78. 77.2
    Petak I, Tillman DM, Houghton JA: P53-dependence of Fas induction amd acute apoptosis in response to 5-fluorouracilleucovorin in human colon carcinoma cell lines. Clin Cancer Res 6:4432–4441, 2000.PubMedGoogle Scholar
  79. 78.2
    Siltonen T, Mantymaa P, Saily M, et al: Etoposide-induced apoptosis is not associated with the fas pathway in acute myeloblastic leukemia cells. Leukemia Res 24:281–288, 2000.CrossRefGoogle Scholar
  80. 79.2
    Tolomeo M, Dusonchet T, Meli M, et al: The CD95/CD95 ligand system is not the major effector in anticancer drug-mediated apoptosis. Cell Death Diff 5:735–742, 1998.CrossRefGoogle Scholar
  81. 80.2
    Shao R-G, Cao C-X, Nieves-Neira W, et al: Activation of the Fas pathway independently of Fas ligand during apoptosis induced by camptothecin in p53 mutant colon carcinoma cells. Oncogene 20:1852–1859, 2001.PubMedCrossRefGoogle Scholar
  82. 81.2
    Wieder T, Essmann F, Prokop A, et al: Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95/Fas receptor-ligand interaction and occurs downstream of caspase-3. Blood 97:1378–1387, 2001.PubMedCrossRefGoogle Scholar
  83. 82.2
    Wesselborg S, Engels IH, Rossmann E, et al: Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction. Blood 93:3053–3063, 1999.PubMedGoogle Scholar
  84. 83.2
    Tang D, Lahti JM, Kidd VJ: Caspase-8 activation and Bid cleavage contribute to MCF7 cellular execution in a caspase3-dependent manner during staurosporine-mediated apoptosis. J Biol Chem 275:9303–9307, 2000.PubMedCrossRefGoogle Scholar
  85. 84.2
    Ferreira CG, Span SW Peters GJ: Chemotherapy triggers apoptosis in a caspase-8-dependent and mitochondria-controlled manner in the non-small cell lung cancer cell line NCIH460. Cancer Res 60:7133–7141, 2000.PubMedGoogle Scholar
  86. 85.2
    Kinoshita H, Yoshikawa H, Shiiki K, et al: Cisplatin (CDDP) sensitizes human osteosarcoma cells to Fas/CD95-mediated apoptosis by downregulating FLIP-L expression. In J Cancer 88:986–991, 2000.Google Scholar
  87. 86.2
    Tang D, Lahti JM, Grenet J, et al: Cycloheximide-induced T-cell death is mediated by a Fas-associated death domaindependent mechanism. J Biol Chem 274:7245–7252, 1999.PubMedCrossRefGoogle Scholar
  88. 87.2
    Dorrie J, Schuh W Keil A, et al: Regulation of CD95 expression and CD95-mediated cell death by interferon-gamma in acute lymphoblastic leukemia with chromosomal translocation t(4;ll). Leukemia 13:1539–1547, 1999.PubMedCrossRefGoogle Scholar
  89. 88.2
    Griffith TS, Chin WA, Jackson GC, et al: Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol 161:2833–2840, 1998.PubMedGoogle Scholar
  90. 89.2
    Bretz JD, Rymaszewski M, Arscott PL, et al: TRAIL death pathway expression and induction in thyroid follicular cells. J Biol Chem 274:23627–23632, 1999.PubMedCrossRefGoogle Scholar
  91. 90.2
    Kataoka T, Schroter M, Hahne M, et al: FLIP prevents apoptosis induced by death receptors but not by perforin/granzyme B, chemotherapeutic drugs, and gamma radiation. J Immunol 161:3936–3942, 1998.PubMedGoogle Scholar
  92. 91.2
    Los M, Herr I, Friesen C, et al: Cross-resistance of CD95- and drug-induced apoptosis as a consequence of deficient activation of caspases (ICE/Ced-3 proteases). Blood 90:3118–3129, 1997.PubMedGoogle Scholar
  93. 92.2
    Boesen-de Cock JG, Tepper AD, de Vries E, et al: Common regulation of apoptosis signaling induced by CD95 and the DNA-damaging stimuli etoposide and -radiation downstream from caspase-8 activation. J Biol Chem 274:14255–14261, 1999.CrossRefGoogle Scholar
  94. 93.2
    Sun X-M, MacFarlane M, Zhuang J, et al: Distinct caspase cascades are initiated in receptor-mediated and chemicalinduced apoptosis. J Biol Chem 274:50530–50560, 1999.Google Scholar
  95. 94.2
    Wu X-Y, Mizutami Y, Kakehi Y, et al: Enhancement of Fasmediated apoptosis in renal cell carcinoma cells by adriamycin. Cancer Res 60:2912–2918, 2000.PubMedGoogle Scholar
  96. 95.2
    Tamura T, Aoyama N, Saya H, et al: Induction of Fas-mediated apoptosis in p53-transfected human colon carcinoma cells. Oncogene, 11:1939–1946, 1995.PubMedGoogle Scholar
  97. 96.2
    Owen-Sachaub LB, Zhang W Cusack JC, et al: Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol 15:3032–3040, 1995.Google Scholar
  98. 97.2
    Rakkar ANS, Katayos Y, Kim M, et al: A novel adenoviral vector expressing human Fas/CD95/APO-l enhances p53-mediated apoptosis. Cell Death Diff 6:326–333, 1999.CrossRefGoogle Scholar
  99. 98.2
    Fukazawa T, Fujiwara T, Morimoto Y, et al: Differential involvement of the CD95 (Fas/APO-1) receptor/ligand system on apoptosis induced by the wild-type p53 gene transfer in human cancer cells. Oncogene, 18:2189–2199, 1999.PubMedCrossRefGoogle Scholar
  100. 99.2
    Shimizu M, Yoshimoto T, Nagata S, et al: A trial to kill tumor cells through Fas (CD95)-mediated apoptosis in vivo. Biochem Biophys Res Commun 228:375–379, 1996.PubMedCrossRefGoogle Scholar
  101. 100.2
    Wu GS, Burns TF, McDonald ER 3rd,et al: KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 17:141–143, 1997.PubMedCrossRefGoogle Scholar
  102. 101.2
    Nagane M, Pan G, Weddle JJ, et al: Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factorrelated apoptosis-inducing ligand in vitro and in vivo. Cancer Res 60:847–853, 2000.PubMedGoogle Scholar
  103. 102.2
    Herr I, Wilhelm D, Bohler T, et al: JNK/SAPK activity is not sufficient for anticancer therapy-induced apoptosis involving CD95-L, TRAIL and TNF-alpha. Int J Cancer 80:417–424, 1999.PubMedCrossRefGoogle Scholar
  104. 103.2
    Friesen C, Fulda S, Debatin KM: Induction of CD95 ligand and apoptosis by doxorubicin is modulated by the redox state in chemosensitiveand drug-resistant tumor cells. Cell Death Differ 6:471–480, 1999.PubMedCrossRefGoogle Scholar
  105. 104.2
    Herr I, Wilhelm D, Bohler T, et al: Activation of CD95 (APO1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J 16:6200–6208, 1997.PubMedCrossRefGoogle Scholar
  106. 105.2
    Boland MP, Foster SJ, O’Neill LAJ: Daunorubicin activates NF-kB and induces KB-dependent gene expression in HL-60 promyelocytic and Jurkat T lymphoma cells. J Biol Chem 272:12952–12960, 1997PubMedCrossRefGoogle Scholar
  107. 106.2
    Miyamoto S, Verma IM: Rel/NF-kappaB/IkappaB story. Adv Cancer Res 66:255–292, 1995.PubMedCrossRefGoogle Scholar
  108. 107.2
    Baldwin AS: The NF-kappaB and I kappaB proteins: new discoveries and insights. Ann Rev Immunol 14:649–683, 1996.CrossRefGoogle Scholar
  109. 108.2
    Chen Z, Hagler J, Palombella VJ, et al: Signal-induced sitespecific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes and Dev 9:1586–1597, 1995.PubMedCrossRefGoogle Scholar
  110. 109.2
    Karin M:The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 270:16483–16486, 1995.PubMedGoogle Scholar
  111. 110.2
    Kyriakis J, Banerjee P, Nikolakaki E, et al: The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369:156–160, 1994.PubMedCrossRefGoogle Scholar
  112. 111.2
    Minden A, Lin A, McMahon M, et al: Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science 266:1719–1723, 1994.PubMedCrossRefGoogle Scholar
  113. 112.2
    Derijard B, Hibi M, Wu I-H, et al: JNK 1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76:1025–1037, 1994.PubMedCrossRefGoogle Scholar
  114. 113.2
    Chen Y-R, Wang X, Templeton D, et al: The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and radiation. J Biol Chem 271:31929–31936, 1996.PubMedCrossRefGoogle Scholar
  115. 114.2
    Kharbanda S, Ren R, Pandey P, et al: Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Nature 376:785–788, 1995.PubMedCrossRefGoogle Scholar
  116. 115.2
    Van Dam H, Wilhelm D, Herri, I, et al: ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. EMBO J 14:1798–1811, 1995.PubMedGoogle Scholar
  117. 116.2
    Yu R, Shtil AA, Tan T-H, et al: Adriamycin activates c-jun Nterminal kinase in human leukemia cells: a relevance to apoptosis. Cancer Lett 107:73–81, 1996.PubMedCrossRefGoogle Scholar
  118. 117.2
    Scimiya H Mashima T, Toho M, et al: c-Jun NH2-terminal kinase-mediated activation of interleukin-1β converting enzyme/CED-3-like protease during anticancer drug-induced apoptosis. J Biol Chem 272:4631–4636, 1997.CrossRefGoogle Scholar
  119. 118.2
    Sanchez-Perez I, Murguia JR, Perona R: Cisplatin induces a persistent activation of JNK that is related to cell death. Oncogene 16:533–540, 1998.PubMedCrossRefGoogle Scholar
  120. 119.2
    Rudel T, Zenke FT, Chuang T-H, et al: Cutting edge: p21-activated kinase (PAK) is required for Fas-induced JNK activation in Jurkat cells. J Immunol 160:7–11, 1998.PubMedGoogle Scholar
  121. 120.2
    Liu Z-G, Baskaran C, Lee-Choe ET, et al: Three distinct signaling responses by murine fibroblasts to genotoxic stress. Nature 384:273–276, 1996.PubMedCrossRefGoogle Scholar
  122. 121.2
    Enari M, Sakahiera H, Yokoyama H, et al: A caspase-activated Dnase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:43, 1998.PubMedCrossRefGoogle Scholar
  123. 122.2
    Lee FS, Hagler J, Chen CJ, et al: Activation of the IkBk kinase complex by MEKK1, a kinase of the JNK pathway. Cell 88:213–222, 1997.PubMedCrossRefGoogle Scholar
  124. 123.2
    Bessho R, Matsubara K, Kubota M, et al: Pyrrolidine dithiocarbamate, a potent inhibitor of nuclear factor kB (NF-kB) activation, prevents apoptosis in human promyelocytic leukemia HL-60 cells and thymocytes. Biochem Pharmacol 48:1883–1889, 1994.PubMedCrossRefGoogle Scholar
  125. 124.2
    Piret B, Piette J: Topoisomerase poisons activate the transcription factor NF-kB in ACH-2 and CEM cells, ucl Acids Res 24:4242–4248, 1996.CrossRefGoogle Scholar
  126. 125.2
    Brach MA, Kharbanda SM, Herrmann F, et al: Activation of the transcription factor kappaB in human KG-1 myeloid leukemia cells treated with 1-beta-D-arabinofuranosylcytosine. Mol Pharmacol 41:60–63, 1992.PubMedGoogle Scholar
  127. 126.2
    Testi R. Sphingomyelin breakdown and cell fate. Trends Biochem Sci 21:468–471, 1996.PubMedCrossRefGoogle Scholar
  128. 127.2
    Bose R, Verheij M, Haimovitz-Friedman A, et al: Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82:405–414. 1995.PubMedCrossRefGoogle Scholar
  129. 128.2
    Hannun YA: Functions of ceramide in coordinating cellular responses to stress. Science 274:1855–1859, 1996.PubMedCrossRefGoogle Scholar
  130. 129.2
    Hannun YA, Obeid LM: Mechanisms of ceramide-mediated apoptosis. Adv Exp Med Biol 407:145–149, 1997.PubMedGoogle Scholar
  131. 130.2
    Mathias S, Pena LA, Kolesnick RN: Signal transduction of stress via ceramide. Biochem J 335:465–480, 1998.PubMedGoogle Scholar
  132. 131.2
    Verheij M, Bose R, Lin XH, et al: Requirement for ceramideinitiated SAPK/JNK signalling in stress-induced apoptosis. Nature 380:75–79, 1996.PubMedCrossRefGoogle Scholar
  133. 132.2
    Wiegmann K, Schutze S, Machleidt T, et al: Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell 78:1005–1015, 1994.PubMedCrossRefGoogle Scholar
  134. 133.2
    Spiegel S, Foster D, Kolesnick R: Signal transduction through lipid second messengers. Curr Opin Cell Biol 8:159–167, 1996.PubMedCrossRefGoogle Scholar
  135. 134.2
    Hirschberg K, Rodger J, Futerman AH: The long-chain sphingoid base of sphingolipids is acylated at the cytosolic surface of the endoplasmic reticulum in rat liver. Biochem J 290:751–757, 1993.PubMedGoogle Scholar
  136. 135.2
    Shimeno H, Soeda S, Yasukouchi M, et al: Fatty acyl-Co A: sphingosine acyltransferase in bovine brain mitochondria: its solubilization and reconstitution onto the membrane lipid liposomes. Biol Pharm Bull 18:1335–1339, 1995.PubMedGoogle Scholar
  137. 136.2
    Adam-Klages S, Schwandner R, Adam D, et al: Distinct adapter proteins mediate acid versus neutral sphingomyelinase activation through the p55 receptor for tumor necrosis factor. J Leukoc Biol 63:678–682, 1998.PubMedGoogle Scholar
  138. 137.2
    Schwandner R, Wiegmann K, Bernardo K, et al: TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase. J Biol Chem 273:5916–5922, 1998.PubMedCrossRefGoogle Scholar
  139. 138.2
    Wiegmann K, Schwandne R, Krut O, et al: Requirement of FADD for tumor necrosis factor-induced activation of acid sphingomyelinase. J Biol Chem 274:5267–5270, 1999.PubMedCrossRefGoogle Scholar
  140. 139.2
    Cuvillier O, Edsall L, Spiegel S: Involvement of sphingosine in mitochondria-dependent Fas-induced apoptosis of type II Jurkat T cells. J Biol Chem 275:15691–15700, 2000.PubMedCrossRefGoogle Scholar
  141. 140.2
    Cecconi F, Alvarez-Bolado G, Meyer BI, et al: Apafl (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94:727–737, 1998.PubMedCrossRefGoogle Scholar
  142. 141.2
    Susin SA, Zamzami N, Castedo M, et al: The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-l/CD95and ceramide-induced apoptosis. J Exp Med 186:25–37, 1997.PubMedCrossRefGoogle Scholar
  143. 142.2
    De Maria R, Lenti L, Malisan F, et al: Requirement for GD3 ganglioside in CD95and ceramide-induced apoptosis. Science 277:1652–1655, 1997.PubMedCrossRefGoogle Scholar
  144. 143.2
    Zhou H, Summers SA, Birnbaum MJ, et al: Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis. J Biol Chem 273:16568–16575, 1998.PubMedCrossRefGoogle Scholar
  145. 144.2
    Boland MP, Foster SJ, O’Neill LA: Daunorubicin activates NFkappaB and induces kappaB-dependent gene expression in HL-60 promyelocytic and Jurkat T lymphoma cells. J Biol Chem 272:12952–12960, 1997.PubMedCrossRefGoogle Scholar
  146. 145.2
    Dbaibo GS, Pushkareva MY, Rachid RA, et al: p53-dependent ceramide response to genotoxic stress. J Clin Invest 102:329–339, 1998.PubMedCrossRefGoogle Scholar
  147. 146.2
    Sawai H, Okazaki T, Yamamoto H, et al: Requirement of AP-1 for ceramide-induced apoptosis in human leukemia HL-60 cells. J Biol Chem 270:27326–27331, 1995.PubMedCrossRefGoogle Scholar
  148. 147.2
    Scaffidi C, Schmitz I, Zha J, et al: Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem 274:22532–22538, 1999.PubMedCrossRefGoogle Scholar
  149. 148.2
    Cuvillier O, Pirianov G, Kleuser B, et al: Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381:800–803, 1996.PubMedCrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2001

Authors and Affiliations

  1. 1.Division of Experimental Hematology, Department of Hematology-OncologySt. Jude Children’s Research HospitalMemphisUSA

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