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The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells

Oncogene volume 21, pages 708–718 (2002)Cite this article

Abstract

Human melanoma cells growth arrest irreversibly, lose tumorigenic potential and terminally differentiate after treatment with a combination of fibroblast interferon (IFN-β) and the protein kinase C activator mezerein (MEZ). Applying subtraction hybridization to this model differentiation system permitted cloning of melanoma differentiation associated gene-7, mda-7. Expression of mda-7 inversely correlates with melanoma development and progression, with elevated expression in normal melanocytes and nevi and increasingly reduced expression in radial growth phase, vertical growth phase and metastatic melanoma. When expressed by means of a replication incompetent adenovirus (Ad.mda-7) growth of melanoma, but not normal early passage or immortal human melanocytes, is dramatically suppressed and cells undergo programmed cell death (apoptosis). Infection of metastatic melanoma cells with Ad.mda-7 results in an increase in cells in the G2/M phase of the cell cycle and changes in the ratio of pro-apoptotic (BAX, BAK) to anti-apoptotic (BCL-2, BCL-XL) proteins. Ad.mda-7 infection results in a temporal increase in mda-7 mRNA and intracellular MDA-7 protein in most of the melanocyte/melanoma cell lines and secretion of MDA-7 protein is readily detected following Ad.mda-7 infection of both melanocytes and melanoma cells. The present studies document a differential response of melanocytes versus melanoma cells to ectopic expression of mda-7 and support future applications of mda-7 for the gene-based therapy of metastatic melanoma.

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References

  • Adams JM, Cory S . 1998 Science 281: 1322–1326

  • Armstrong BK, Kricker A . 1994 Cancer Surv. 19–20: 219–240

  • Chaiken IM, Williams WY . 1996 Trends Biotech. 14: 369–375

  • Cirielli C, Riccioni T, Yang C, Pili R, Gloe T, Chang J, Inyaku K, Passaniti A, Capogrossi MC . 1995 Intl. J. Cancer 63: 673–679

  • Clark W . 1991 Br. J. Cancer 64: 631–644

  • Dumoutier L, Leemans, Lejeune D, Kotenko SV, Renauld J-C . 2001 J. Immunol. 167: 3545–3549

  • Ekmekcioglu S, Ellerhorst J, Mhashilkar AM, Sahin AA, Read CM, Prieto VG, Chada S, Grimm EA . 2001 Intl. J. Cancer 94: 54–59

  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B . 1993 Cell 75: 817–825

  • Evan G, Littlewood T . 1998 Science 281: 1317–1322

  • Falck-Pedersen E, Heinflink M, Alvira M, Nussenzveig DR, Gershengorn MC . 1994 Mol. Pharmacol. 45: 684–689

  • Fechner H, Wang X, Wang H, Jansen A, Pauschinger M, Scherubl H, Bergelson JM, Schultheiss HP, Poller W . 2000 Gene Ther. 7: 1954–1968

  • Fisher PB, Prignoli DR, Hermo Jr H, Weinstein IB, Pestka S . 1985 J. Interferon Res. 5: 11–22

  • Gallagher G, Dickensheets H, Eskdale J, Izotova LS, Mirochnitchenko OV, Peat JD, Vasquez N, Pestka S, Donnelly RP, Kotenko SV . 2000 Genes Immun. 1: 442–450

  • Giovanella BC, Stehlin JS, Santamaria C, Yim So, Morgan AC, Williams LJ, Leibovitz A, Fialkow PY, Mumford DM . 1976 J. Natl. Cancer Inst. 56: 1131–1142

  • Graham FL, Smiley J, Russell WC, Nairn R . 1977 J. Gen. Virol. 36: 59–72

  • Graham GM, Guarini L, Moulton TA, Datta S, Ferrone S, Giacomini P, Kerbel RS, Fisher PB . 1991 Cancer Immunol. Immunother. 32: 382–390

  • Green DR, Reed JC . 1998 Science. 281: 1309–1312

  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ . 1993 Cell 75: 805–816

  • Herlyn M . 1990 Cancer Metast. 9: 101–112

  • Hidaka C, Milano E, Leopold PL, Bergelson JM, Hackett NR, Finberg RW, Wickham TJ, Kovesdi I, Roelvink P, Crystal RG . 1999 J. Clin. Invest. 103: 579–587

  • Huang EY, Madireddi MT, Gopalkrishnan RV, Leszczyniecka M, Su Z-z, Lebedeva IV, Kang D-c, Jiang H, Lin JJ, Alexandre D, Chen Y, Vozhilla N, Mei MX, Christiansen KA, Sivo F, Goldstein NI, Mhashilkar AB, Chada S, Huberman E, Pestka S, Fisher PB . 2001 Oncogene 20: 7051–7063

  • Huang F, Adelman J, Jiang H, Goldstein NI, Fisher PB . 1999a Oncogene 18: 3546–3552

  • Huang F, Adelman J, Jiang H, Goldstein NI, Fisher PB . 1999b Gene 236: 125–131

  • Jiang H, Fisher PB . 1993 Mol. Cell. Different. 1: 285–299

  • Jiang H, Lin J, Fisher PB . 1994 Mol. Cell. Different. 2: 221–239

  • Jiang H, Lin JJ, Su Z-z, Goldstein NI, Fisher PB . 1995a Oncogene 11: 2477–2486

  • Jiang H, Lin J, Su Z-z, Kerbel RS, Herlyn M, Weissman RB, Welch DR, Fisher PB . 1995b Oncogene 10: 1855–1864

  • Jiang H, Lin J, Young S-m, Goldstein NI, Waxman S, Davila V, Chellappan SP, Fisher PB . 1995c Oncogene 11: 1179–1189

  • Jiang H, Su Z-z, Boyd J, Fisher PB . 1993 Mol. Cell. Different. 1: 41–66

  • Jiang H, Su Z-z, Lin JJ, Goldstein NI, Young CSH, Fisher PB . 1996 Proc. Natl. Acad. Sci. USA 93: 9160–9165

  • Kerbel RS, Man MS, Dexter D . 1984 J. Natl. Cancer Inst. 72: 93–108

  • Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, Pestka S . 2001 J. Biol. Chem. 276: 2725–2732

  • Leszczyniecka M, Roberts T, Dent P, Grant S, Fisher PB . 2001 Pharmacol. Therapeut. 90: 105–156

  • Li D, Duan L, Friemuth P, O'Malley Jr BW . 1999 Clin. Cancer Res. 5: 4175–4181

  • Lu C, Kerbel RS . 1994 Curr. Opin. Oncol. 6: 212–220

  • Madireddi MT, Dent P, Fisher PB . 2000a Oncogene 19: 1362–1368

  • Madireddi MT, Dent P, Fisher PB . 2000b J. Cell. Physiol. 185: 36–46

  • Madireddi MT, Su Z-z, Young CSH, Goldstein NI, Fisher PB . 2000c Adv. Exp. Med. Biol. 465: 239–261

  • Melber K, Zhu G, Diamond L . 1989 Cancer Res. 49: 3650–3655

  • McGrory WJ, Bautista DS, Graham FL . 1988 Virology 163: 14–617

  • Mhashilkar AM, Schrock RD, Hindi M, Liao J, Sieger K, Kourouma F, Zou-Yang XH, Onishi E, Takh O, Vedvick TS, Fanger F, Stewart L, Watson GJ, Snary D, Fisher PB, Saeki T, Roth JA, Ramesh R, Chada S . 2001 Mol. Med. 7: 271–282

  • Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR . 1994 Exptl. Cell Res. 211: 90–98

  • Pearson AS, Koch PE, Atkinson N, Xiong M, Finberg RW, Roth JA, Fang B . 1999 Clin. Cancer Res. 5: 4208–4213

  • Saeki T, Mhashilkar A, Chada S, Branch C, Roth JA, Ramesh R . 2000 Gene Ther. 7: 2051–2057

  • Su Z-z, Goldstein NI, Jiang H, Wang M-N, Duigou GJ, Young CSH, Fisher PB . 1999 Proc. Natl. Acad. Sci. USA 96: 15115–15120

  • Su Z-z, Madireddi MT, Lin JJ, Young CSH, Kitada S, Reed JC, Goldstein NI, Fisher PB . 1998 Proc. Natl. Acad. Sci. USA 95: 14400–14405

  • Su Z-z, Lin J, Prewett M, Goldstein NI, Fisher PB . 1995 Anticancer Res. 15: 1841–1848

  • Su Z-z, Shi Y, Fisher PB . 1997 Proc. Natl. Acad. Sci. USA 94: 9125–9130

  • Thornberry NA, Lazebnik Y . 1998 Science 281: 1312–1316

  • Volkert FC, Young CSH . 1983 Virology 125: 175–193

  • Waxman S (ed) . 1996 Differentiation Therapy Rome, Italy: Serono Symposium Publications pp 1–528

    Google Scholar 

  • Wilson MR . 1998 Cell Death Differ. 5: 646–652

  • Xie MH, Aggarwal S, Ho WH, Foster J, Zhang Z, Stinson J, Wood WI, Goddard AD, Gurney AL . 2000 J. Biol. Chem. 275: 31335–31339

  • Yang FC, Merlino G, Chin L . 2001 Semin. Cancer Biol. 11: 261–268

  • Yang Z-Y, Perkins ND, Ohno O, Nabel EG, Nabel GJ . 1995 Nat. Med. 1: 1052–1056

  • Young IT . 1977 J. Histochem. Cytochem. 25: 935–941

  • Zhang R, Tan Z, Liang P . 2000 J. Biol. Chem. 275: 24436–24443

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Acknowledgements

The present research was supported in part by National Cancer Institute Grants CA35675 and CA87170, an award from the Samuel Waxman Cancer Research Foundation and the Michael and Stella Chernow Endowment. We thank Dr Sunil Chada, Introgen Therapeutics Inc., TX, for providing MDA-7 polyclonal antibody and CAR monoclonal antibody. PB Fisher is the Michael and Stella Chernow Urological Cancer Research Scientist in the Departments of Urology, Pathology and Neurosurgery.

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Author notes

  1. Irina V Lebedeva and Zao-zhung Su: IV Lebedeva and Z-z Su contributed equally to this manuscript

Authors and Affiliations

  1. Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, 10032, NY, USA

    Irina V Lebedeva, Zao-zhung Su, Yonmee Chang & Paul B Fisher

  2. Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, 10032, NY, USA

    Irina V Lebedeva, Zao-zhung Su, Yonmee Chang & Paul B Fisher

  3. The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California, 92037, CA, USA

    Shinichi Kitada & John C Reed

  4. Department of Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, 10032, NY, USA

    Paul B Fisher

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  1. Irina V Lebedeva
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Correspondence to Paul B Fisher.

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Lebedeva, I., Su, Zz., Chang, Y. et al. The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells. Oncogene 21, 708–718 (2002). https://doi.org/10.1038/sj.onc.1205116

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