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Targeting cancer cell death with a bcl-xS adenovirus

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Summary

Transformation is a complex cellular process that requires several genetic abnormalities. In many cases, one of these abnormalities is an inhibition of PCD, which provides a selective advantage for tumor cells. This has been recently shown in an in vivo model, where overexpression of Bcl-xL is a crucial step in the progression from hyperplasia to neoplasia and is accompanied by a significant decrease in tumor apoptosis [56].

Frequently, overexpression of a member of the Bcl-2 family results in a block in cell death and appears to nullify many built-in cellular defense mechanisms against cancer. Such a block presents a problem because radiation and chemotherapy, standard cancer treatments, ultimately exert their effect by induction of apoptosis and would also be made less effective. Therefore, to better treat cancer it may be necessary to develop novel methods to overcome the effects of the Bcl-2 family. One way to approach this problem is to target the cause - the molecular machinery that allows a cancer cell to survive. Advances in our understanding of apoptosis has identified the Bcl-2 family as a mediator of most apoptosis pathways, including those initiated by oncogenes, tumor suppressor genes, growth factor withdrawal, and external damaging signals. Therefore, functional inhibition of Bcl-2 family members is lethal to many cancer cells. Using gene transfer technology, we can now deliver genes that accomplish this goal. Further investigation will reveal whether this translates to improved therapy in the future.

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References

  1. Angel P, Karin M (1991) The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1072: 129

    Google Scholar 

  2. Armelin HA, Armelin MCS, Kelly K, Stewart T, Leder P, Cochran BH, Stiles CD (1984) Functional role forc-myc in mitogenic response to platelet-derived growth factor. Nature 310: 655

    Google Scholar 

  3. Baffy G, Miyashita T, Williamson JR, Reed JC (1993) Apoptosis induced by withdrawal of interleukin3 (IL-3) from an IL-3-dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production. J Biol Chem 268: 6511

    Google Scholar 

  4. Bissonnette RP, Echeverri F, Mahnoubi A, Green DR (1992) Apoptotic cell death induced byc-myc is inhibited bybcl-2. Nature 359: 552

    Google Scholar 

  5. Blackwell TK, Kretzner L, Blackwood EM, Eisenman RN, Weintraub H (1990) Sequence-specific DNA binding by the c-myc protein. Science 250: 1149

    Google Scholar 

  6. Blackwood EM, Eisenman RN (1991) Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science 251: 1211

    Google Scholar 

  7. Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB (1993)bcl-x, abcl-2 related gene that functions as a dominant regulator of apoptotic cell death. Cell 74: 597

    Google Scholar 

  8. Boyd JM, Gallo GJ, Elangovan B, Houghton AB, Malstrom S, Avery GJ, Ebb RG, Subramanian T, Chittenden T, Lutz RJ, Chinnadurai G (1995) Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family and interacts with viral and cellular survival-promoting proteins. Oncogene 11: 1921

    Google Scholar 

  9. Brenner MK, Rill DR, Moen RC, Krance RA, Mirro J, Anderson WF, Ihle JN (1993) Gene-marking to trace origin of relapse after autologous bone-marrow transplantation. Lancet 341: 85

    Google Scholar 

  10. Buttyan R, Zakeri Z, Lockshin R, Wolgemuth D (1988) Cascade induction ofc-fos, c-myc, and heat shock 70 K transcripts during regression of the rat ventral prostate gland. Mol Endocrinol 2

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

    Google Scholar 

  12. Carson WE, Haldar S, Baiocchi RA, Croce CM, Caligiuri MA (1994) The c-kit ligand suppresses apoptosis of human natural killer cells through the upregulation of bcl-2. Proc Natl Acad Sci USA 91: 7553

    Google Scholar 

  13. Castle VP, Heidelberger KP, Bromberg J, Ou X, Dole M, Nunez G (1993) Expression of the apoptosis-suppressing protein Bcl-2 in neuroblastoma is associated with poor stage disease, unfavorable histology and N-myc amplification. Am J Pathol 143: 1543

    Google Scholar 

  14. Chinnaiyan AM, Orth K, O'Rourke K, Duan H, Poirier GG, Dixit VM (1996) Molecular ordering of the cell death pathway. J Biol Chem 271: 4573

    Google Scholar 

  15. Chinnaiyan AM, O'Rourke K, Lane BR, Dixit VM (1997) Interaction of CED-4 with CED-4 and CED-9: a molecular framework for cell death. Science 275: 1122

    Google Scholar 

  16. Chittenden T, Harrington EA, O'Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC (1995) Induction of apoptosis by the Bcl-2 homologue Bak. Nature 374: 733

    Google Scholar 

  17. Chiu R, Boyle WJ, Meek W, Smeal T, Hunter T, Karin M (1988) The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell 54: 541

    Google Scholar 

  18. Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH (1993) Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362: 849

    Google Scholar 

  19. Clarke MF, Apel IJ, Benedict MA, Eipers PG, Sumantran V, Gonzalez-Garcia M, Doedens M, Fukanaga-Johnson N, Davidson B, Dick JE, Minn AJ, Boise LH, Thompson CB, Wicha M, Nunez G (1995) A recombinant bcl-xS adenovirus selectively induces apoptosis in cancer cells but not in normal bone marrow cells. Proc Natl Acad Sci USA 92: 11024

    Google Scholar 

  20. Cleary ML, Smith SD, Sklar J (1986) Cloning and structural analysis of cDNAs forbcl-2 and a hybridbcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47: 19

    Google Scholar 

  21. Collins MKL, Perkins GR, Rodriguez-Tarduchy G, Nieto MA, Lopez-Rivas A (1994) Growth factors as survival factors: regulation of apoptosis. Bioessays 16: 133

    Google Scholar 

  22. Colombel M, Symmans F, Gil S, O'Toole KM, Chopin D, Benson M, Olsson CA, Korsmeyer SJ, Buttyan R (1993) Detection of the apoptosis-suppressing protein bcl-2 in hormone-refractory human prostate cancers. Am J Pathol 143: 390

    Google Scholar 

  23. Colotta F, Polentarutti N, Sironi M, Mantovani A (1992) Expression and involvement of c-fos and c-jun protooncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines. J Biol Chem 267: 18278

    Google Scholar 

  24. Dole MG, Kasty R, Cooper MJ, Thompson CB, Nunez G, Castle VP (1995) Bcl-xL is expressed in neuroblastoma cells and modulates chemotherapy-induced apoptosis. Anticancer Res 55: 2576

    Google Scholar 

  25. Eilers M, Schirm S, Bishop JM (1991) The Myc protein activates transcription of the alpha-prothymosin gene. EMBO J 10: 133

    Google Scholar 

  26. El-Deirt WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817

    Google Scholar 

  27. Ellis H, Horvitz HR (1986) Genetic control of programmed cell death in the nematodeC. elegans. Cell 44: 817

    Google Scholar 

  28. Ellis RE, Yuan J, Horvitz HR (1991) Mechanisms and functions of cell death. Annu Rev Cell Biol 7: 663

    Google Scholar 

  29. Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC (1992) Induction of apoptosis in fibroblasts byc-myc protein. Cell 69: 119

    Google Scholar 

  30. Fanidi A, Harrington EA, Evan GI (1992) Cooperative interaction betweenc-myc andbcl-2 proto-oncogenes. Nature 359: 554

    Google Scholar 

  31. Farrow SN, White JHM, Martinou I, Raven T, Pun K, Grinham CJ, Martinou J, Brown R (1995) Cloning of abcl-2 homologue by interaction with adenovirus E1B 19 K. Nature 374: 731

    Google Scholar 

  32. Fisher DE (1994) Apoptosis in cancer therapy: crossing the threshold. Cell 78: 539

    Google Scholar 

  33. Fukunaga-Johnson N, Ryan JJ, Wicha M, Nunez G, Clarke MF (1995) Bcl-2 protects murine erythroleukemia cells from p53-dependent and -independent radiation-induced cell death. Carcinogenesis 16: 1761

    Google Scholar 

  34. Harrington EA, Bennett MR, Fanidi A, Evan GI (1994) c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J 13: 3286

    Google Scholar 

  35. Hartmann O, Benhamou E, Beaujean F, Kalifa C, Lejars O, Patte C, Behard C, Flamant F, Thyss A, Deville A, Vannier JP, Pautard-Muchemble B, Lemerle J (1987) Repeated high-dose chemotherapy followed by purged autologous bone marrow transplantation as consolidation therapy in metastatic neuroblastoma. J Clin Oncol 5: 1205

    Google Scholar 

  36. Haupt Y, Rowan S, Shaulian E, Vousden KH, Oren M (1995) Induction of apoptosis in HeLa cells bytrans-activation-deficient p53. Genes Dev 9: 2170

    Google Scholar 

  37. Head DR, Kennedy PS, Goyette RE (1979) Metastatic neuroblastoma in bone marrow aspirate smears. Am J Clin Pathol 72: 1008

    Google Scholar 

  38. Hengartner M, Ellis R, Horvitz HR (1992)C. elegans geneced-9 protects cells from programmed cell death. Nature 356: 494

    Google Scholar 

  39. Hengartner MO, Horvitz HR (1994)C. elegans cell survival geneced-9 encodes a functional homolog of the mammalian proto-oncogenebcl-2. Cell 76: 665

    Google Scholar 

  40. Hermeking H, Fick D (1994) Mediation of c-Myc-induced apoptosis by p53. Science 265: 2091

    Google Scholar 

  41. Hockenbery DM, Oltvai ZN, Yin X, Milliman CL, Korsmeyer SJ (1993) Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75: 241

    Google Scholar 

  42. Irmler M, Hofmann K, Vaux D, Tschopp J (1997) Direct physical interaction between theCaenorhabditis elegans ‘death proteins’ CED-3 and CED-4. FEBS Lett 406: 189

    Google Scholar 

  43. Kent SE, Kinzler KW, Bruskin A, Jarosz D, Friedman P, Prives C, Vogelstein B (1991) Identification of p53 as a sequence-specific DNA-binding protein. Science 252: 1708

    Google Scholar 

  44. Kerr JFR, Harmon B, Searle J (1974) An electron-microscope study of cell deletion in the anuran tadpole tail during spontaneous metamorphosis with special reference to apoptosis in striated muscle fibres. J Cell Sci 14: 571

    Google Scholar 

  45. Kessinger A, Armitage JO (1991) The evolving role of autologous peripheral stem cell transplantation following high-dose therapy for malignancies. Blood 77: 211

    Google Scholar 

  46. Kiefer MC, Brauer MJ, Powers VC, Wu JJ, Umansky SR, Tomei LD, Barr PJ (1995) Modulation of apoptosis by the widely distributed Bcl-2 homlogue Bak. Nature 374: 736

    Google Scholar 

  47. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275: 1132

    Google Scholar 

  48. Krajewski S, Tanaka S, Takayama S, Schibler MJ, Fenton W, Reed JC (1993) Investigation of the subcellular distribution of thebcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res 53: 4701

    Google Scholar 

  49. Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB (1992) Wild-type p53 is a cell cycle checkpoint determinant following radiation. Proc Natl Acad Sci USA 89: 7491

    Google Scholar 

  50. Lam M, Dubyak G, Chen L, Nunez G, Miesfeld RL, Distelhorst CW (1994) Evidence that BCL-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes. Proc Natl Acad Sci USA 91: 6569

    Google Scholar 

  51. Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88: 323

    Google Scholar 

  52. Lowe S, Schmitt EM, Smith SW, Osborne BA, Jacks T (1993) p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362: 847

    Google Scholar 

  53. McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, Korsmeyer SJ (1989) bcl-2 immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57: 79

    Google Scholar 

  54. Meikrantz W, Gisselbrecht S, Tam SW, Schlegel R (1994) Activation of cyclin A-dependent protein kinase during apoptosis. Proc Natl Acad Sci USA 91: 3754

    Google Scholar 

  55. Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the humanbax gene. Cell 80: 293

    Google Scholar 

  56. Naik P, Karrim J, Hanahan D (1996) The rise and fall of apoptosis during multistep tumorigenesis: down-modulation contributes to tumor progression from angiogenic progenitors. Genes Dev 10: 2105

    Google Scholar 

  57. Nguyen M, Millar DG, Yong VW, Korsmeyer SJ, Shore GC (1993) Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J Biol Chem 268: 25265

    Google Scholar 

  58. Nunez G, London L, Hockenbery D, Alexander M, McKearn JP, Korsmeyer SJ (1990) Deregulatedbcl-2 gene expression selectively prolongs survival of growth factor-deprived hematopoietic cell lines. J Immunol 144: 3602

    Google Scholar 

  59. Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74: 609

    Google Scholar 

  60. Parodi S, Mancuso T (1996) A general overview of the process of carcinogenesis. Tumori 82: 291

    Google Scholar 

  61. Pietilainen T, Lipponen P, Aaltomaa S, Eskelinen M, Kosma V, Syrjanen K (1995) Expression of c-myc proteins in breast cancer as related to established prognostic factors and survival. Anticancer Res 15: 959

    Google Scholar 

  62. Prendergast G, Ziff E (1991) Methylation-sensitive sequence-specific DNA binding by the c-myc basic region. Science 251: 186

    Google Scholar 

  63. Preston GA, Lyon TT, Yin Y, Lang JE, Solomon G, Annab L, Srinivasan DG, Alcorta DA, Barret JC (1996) Induction of apoptosis by c-Fos protein. Mol Cell Biol 16: 211

    Google Scholar 

  64. Raycroft L, Wu H, Lozano G (1990) Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science 249: 1049

    Google Scholar 

  65. Ross AA, Cooper BW, Lazarus HM, Mackay W, Moss TJ, Ciobanu N, Tallman MS, Kennedy MJ, Davidson NE, Sweet D, Winter C, Akard L, Jansen J, Copelan E, Meagher RC, Herzig RH, Klumpp TR, Kahn DG, Warner NE (1993) Detection and viability of tumor cells in peripheral blood stem cell collections from breast cancer patients using immunocytochemical and clonogenic assay techniques. Blood 82: 2605

    Google Scholar 

  66. Ryan JJ, Prochownik E, Gottlieb CA, Apel IJ, Merino R, Nunez G, Clarke ME (1994)c-myc andbcl-2 modulate p53 function by altering p53 subcellular trafficking during the cell cycle. Proc Natl Acad Sci USA 91: 5878

    Google Scholar 

  67. Sabbatini P, Lin J, Levine AJ, White E (1995) Essential role for p53-mediated transcription in E1A-induced apoptosis. Genes Dev 9: 2184

    Google Scholar 

  68. Schott AF, Apel IJ, Nunez G, Clarke ME (1995) Bcl-xL protects cancer cells from p53-mediated apoptosis. Oncogene 11: 1389

    Google Scholar 

  69. Sentman CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ (1991)bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67: 879

    Google Scholar 

  70. Seto E, Usheva A, Zambetti GP, Momand J, Horikoshi N, Weinmann R, Levine AJ, Shenk T (1992) Wild-type p53 binds to the TATA-binding protein and represses transcription. Proc Natl Acad Sci USA 89: 12028

    Google Scholar 

  71. Sierra A, Lloveras B, Castellsague X, Moreno L, Garcia-Ramirez M, Fabra A (1995) Bcl-2 expression is associated with lymph node metastasis in human dutal breast carcinoma. Int J Cancer 60: 54

    Google Scholar 

  72. Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJT (1989) Antibodies to CD3/T cell receptor complex induce cell death by apoptosis in immature T clls in thymic cultures. Nature 337: 181

    Google Scholar 

  73. Spector MS, Desnoyers S, Hoeppner DJ, Hengartner MO (1997) Interaction between theC. elegans cell-death regulators CED-9 and CED-4. Nature 385: 653

    Google Scholar 

  74. Sumantran V, Ealovega MW, Nunez G, Clarke MF, Wicha MS (1995) Overexpression of Bcl-xs sensitizes MCF-7 cells to chemotherapy induced apoptosis. Cancer Res 55: 2507

    Google Scholar 

  75. Tanaka S, Saito K, Reed JC (1993) Structure-function analysis of the Bcl-2 oncoprotein. J Biol Chem 269: 10920

    Google Scholar 

  76. Tsujimoto Y, Croce CM (1986) Analysis of the structure, transcripts, and protein products ofbcl-2, the gene involved in human follicular lymphoma. Proc Natl Acad Sci USA 83: 5214

    Google Scholar 

  77. Vaux DL, Cory S, Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates withc-myc to immortalize pre-B cells. Nature 335: 440

    Google Scholar 

  78. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75: 229

    Google Scholar 

  79. Vogelstein B (1990) A deadly inheritance. Nature 348: 681

    Google Scholar 

  80. Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9: 138

    Google Scholar 

  81. Wagner AJ, Small MB, Hay N (1993) Myc-mediated apoptosis is blocked by ectopic expression of bcl-2. Mol Cell Biol 13: 2432

    Google Scholar 

  82. Wagner AJ, Kokontis JM, Hay N (1994) Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21wafl/cipl. Genes Dev 8: 2817

    Google Scholar 

  83. Weinberg RA (1991) Tumor suppressor genes. Science 254: 1138

    Google Scholar 

  84. Wu D, Wallen HD, Nunez G (1997) Interaction and regulation of subcellular localization of CED-4 by CED-9. Science 275: 1126

    Google Scholar 

  85. Wu D, Wallen HD, Inohara N, Nunez G (1997) Interaction and regulation of theCaenorhabditis elegans death protease CED-3 by CED-4 and CED-9. J Biol Chem 272: 1

    Google Scholar 

  86. Wyllie AH, Kerr JF, Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68: 251

    Google Scholar 

  87. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ (1995) Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces Bax and promotes cell death. Cell 80: 285

    Google Scholar 

  88. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng T, Jones DP, Wang X (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275: 1129

    Google Scholar 

  89. Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M (1991) Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352: 345

    Google Scholar 

  90. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR (1993) TheC. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-lB-converting enzyme. Cell 75: 641

    Google Scholar 

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  1. Department of Internal Medicine, University of Michigan Medical School, 1500 E. Medical Center Dr., Bldg. Room 4-303, Comprehensive Cancer Center, 48109, Ann Arbor, MI, USA

    Jeffrey S. Han, Max S. Wicha & Michael F. Clarke

  2. Department of Pathology, University of Michigan Medical School, 48109, Ann Arbor, MI, USA

    Gabriel Núñez

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Han, J.S., Núñez, G., Wicha, M.S. et al. Targeting cancer cell death with a bcl-xS adenovirus. Springer Semin Immunopathol 19, 279–288 (1998). https://doi.org/10.1007/BF00787225

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