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Mechanistic aspects of mda-7/IL-24 cancer cell selectivity analysed via a bacterial fusion protein

Oncogene volume 23, pages 7679–7690 (2004)Cite this article

Abstract

The human mda-7/IL-24 gene product is normally expressed in melanocytes and certain lymphocyte populations. Loss of expression, a distinctive feature of many tumor suppressor genes, has been documented at RNA and protein levels in association with melanoma progression both in vitro as well as in human tumor-derived material. The MDA-7/IL-24 protein undergoes post-translational processing, including removal of an amino-terminal 48-residue signal peptide and extensive glycosylation prior to its secretion by producing cells. Its inherent cytokine properties have been documented in multiple reports, which have identified and characterized its cognate receptors and activation of the JAK/STAT signaling pathway following ligand/receptor docking. A notable and incompletely understood property of MDA-7/IL-24 is its ability to induce apoptosis in transformed cells, while having marginal growth suppressive effects on normal primary or immortalized cell lines. MDA-7/IL-24 has been delivered to cells, tumor xenografts and patients in clinical trials via a nonreplicating adenovirus (Ad.mda-7). Studies utilizing eukaryotically expressed and purified MDA-7/IL-24 protein from several sources have recapitulated some of the molecule's reported properties including receptor binding and JAK/STAT activation. Here, we report the properties and characteristics of a bacterially expressed and purified GST-MDA-7 fusion protein. These studies reveal that GST-MDA-7 retains its cancer-selective apoptosis-inducing properties, thereby providing a new reagent that will assist in defining the mechanism of action of this novel cytokine. In addition, retention of tumor-specific activity of GST-MDA-7 suggests that this protein may also have therapeutic applications.

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References

  • Blaszkowsky L . (1998). Front. Biosci., 3, E214–E225.

  • Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, Carollo S, Eagan M, Foster D, Haldeman BA, Hammond A, Haugen H, Jelinek L, Kelly JD, Madden K, Maurer MF, Parrish-Novak J, Prunkard D, Sexson S, Sprecher C, Waggie K, West J, Whitmore TE, Yao L, Kuechle MK, Dale BA and Chandrasekher YA . (2001). Cell, 104, 9–19.

  • Caudell EG, Mumm JB, Poindexter N, Ekmekcioglu S, Mhashilkar AM, Yang XH, Retter MW, Hill P, Chada S and Grimm EA . (2002). J. Immunol., 168, 6041–6046.

  • Chada S, Nemunitais J, Tong AW, Zhang Y, Su D, Mhashilkar A, Yang H, Parker K, Wilson D, Merritt JA and Coffee K . (2001). Cancer Gene Ther., 8, S3.

  • Darnell Jr JE, Kerr IM and Stark GR . (1994). Science, 264, 1415–1421.

  • Fickenscher H, Hor S, Kupers H, Knappe A, Wittmann S and Sticht H . (2002). Trends Immunol., 23, 89–96.

  • Fisher PB, Gopalkrishnan RV, Chada S, Ramesh R, Grimm EA, Rosenfeld MR, Curiel DT and Dent P . (2003). Cancer Biol. Ther., 2, S23–S37.

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

  • Hilgers W and Kern SE . (1999). Genes Chromosomes Cancer, 26, 1–12.

  • Huang EY, Madireddi MT, Gopalkrishnan RV, Leszczyniecka M, Su Z, Lebedeva IV, Kang D, 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 and Fisher PB . (2001). Oncogene, 20, 7051–7063.

  • Jiang H and Fisher PB . (1993). Mol. Cell. Diff., 1, 285–299.

  • Jiang H, Lin J, Su Z-Z and Fisher PB . (1996a). Mol. Cell. Diff., 1, 317–323.

  • Jiang H, Lin JJ, Su Z-Z, Goldstein NI and Fisher PB . (1995). Oncogene, 11, 2477–2486.

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

  • Kisseleva T, Bhattacharya S, Braunstein J and Schindler CW . (2002). Gene, 285, 1–24.

  • Kotenko SV . (2002). Cytokine Growth Factor Rev., 13, 223–240.

  • Lebedeva I, Rando R, Ojwang J, Cossum P and Stein CA . (2000). Cancer Res., 60, 6052–6060.

  • Lebedeva IV, Su Z-Z, Chang Y, Kitada S, Reed JC and Fisher PB . (2002). Oncogene, 21, 708–718.

  • Lorenz M, Heinrich S, Staib-Sebler E, Kohne CH, Wils J, Nordlinger B and Encke A . (2000). Eur. J. Cancer, 36, 957–965.

  • Madireddi MT, Su ZZ, Young CSH, Goldstein NI and Fisher PB . (2000). Adv. Exp. Med. Biol., 465, 239–261.

  • Mhashilkar AM, Stewart AL, Sieger K, Yang HY, Khimani AH, Ito I, Saito Y, Hunt KK, Grimm EA, Roth JA, Meyn RE, Ramesh R and Chada S . (2003). Mol. Ther., 8, 207–219.

  • Namiki S, Tomida T, Tanabe M, Iino M and Hirose K . (2003). Biochem. Biophys. Res. Commun., 305, 592–597.

  • Nemunitais J . (2003). Cancer Gene Therapy, 10, S106.

  • Parrish-Novak J, Xu W, Brender T, Yao L, Jones C, West J, Brandt C, Jelinek L, Madden K, McKernan PA, Foster DC, Jaspers S and Chandrasekher YA . (2002). J. Biol. Chem., 277, 47517–47523.

  • Pestka S, Kotenko SV and Fisher PB . (2003). Encyclopedia of Homones. Henry HL, Norman AW (eds). Academic Press: San Diego, CA, pp. 507–513.

  • Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y and Fisher PB . (2004). Annu. Rev. Immunol., 22, 929–979.

  • Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch CD, Sieger K, Mumm JB, Stewart AL, Boquio A, Dumoutier L, Grimm EA, Renauld JC, Kotenko S and Chada S . (2003). Cancer Res., 63, 5105–5113.

  • Regine WF, John WJ and Mohiuddin M . (1998). Front. Biosci., 3, E186–E192.

  • Rosenberg L . (2000). Drugs, 59, 1071–1089.

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

  • Sarkar D, Su Z-Z, Lebedeva IV, Sauane M, Gopalkrishnan RV, Dent P and Fisher PB . (2002a). Biotechniques Oct. Suppl. 30–39.

  • Sarkar D, Su Z-Z, Lebedeva IV, Sauane M, Gopalkrishnan RV, Valerie K, Dent P and Fisher PB . (2002b). Proc. Natl. Acad. Sci. USA, 99, 10054–10059.

  • Sauane M, Gopalkrishnan RV, Lebedeva I, Mei MX, Sarkar D, Su Z-Z, Kang D-C, Dent P, Pestka S and Fisher PB . (2003a). J. Cell. Physiol., 196, 334–345.

  • Sauane M, Gopalkrishnan RV, Sarkar D, Su Z-Z, Lebedeva IV, Dent P, Pestka S and Fisher PB . (2003b). Cytokine Growth Factor Rev., 14, 35–51.

  • Sauane M, Lebedeva IV, Su Z-Z, Choo H-t, Randolph A, Valerie K, Dent P, Gopalkrishnan RV and Fisher PB . (2004). Cancer Res., 64, 2988–2993.

  • Sieger KA, Mhashilkar AM, Stewart A, Sutton RB, Strube RW, Chen SY, Pataer A, Swisher SG, Grimm EA, Ramesh R and Chada S . (2004). Mol. Ther., 9, 355–367.

  • Smith DB and Johnson KS . (1988). Gene, 67, 31–40.

  • Spiotto MT and Chung TD . (2000). Prostate, 42, 88–98.

  • Su Z-Z, Lebedeva IV, Gopalkrishnan RV, Goldstein NI, Stein CA, Reed JC, Dent P and Fisher PB . (2001). Proc. Natl. Acad. Sci. USA, 98, 10332–10337.

  • Su Z-Z, Lebedeva IV, Sarkar D, Gopalkrishnan RV, Sauane M, Sigmon C, Yacoub A, Valerie K, Dent P and Fisher PB . (2003). Oncogene, 22, 1164–1180.

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

  • Wang M, Tan Z, Zhang R, Kotenko SV and Liang P . (2002). J. Biol. Chem., 277, 7341–7347.

  • Yacoub A, Mitchell C, Brannon J, Rosenberg E, Qiao L, McKinstry R, Linehan WM, Su Z-Z, Sarkar D, Lebedeva IV, Valerie K, Gopalkrishnan RV, Grant S, Fisher PB and Dent P . (2003a). Mol. Cancer Ther., 2, 623–632.

  • Yacoub A, Mitchell C, Hong Y, Schroeder M, Gopalkrishnan RV, Su Z-Z, Gupta P, Sauane M, Lebedeva IV, Curiel DT, Mahasreshti PJ, Rosenfeld MR, Boraddus WC, James CD, Grant S, Fisher PB and Dent P . (2004). Cancer Biol. Ther. in press.

  • Yacoub A, Mitchell C, Lebedeva IV, Sarkar D, Su Z-Z, McKinstry R, Gopalkrishnan RV, Grant S, Fisher PB and Dent P . (2003b). Cancer Biol. Ther., 2, 347–353.

  • Zhan Y, Song X and Zhou GW . (2001). Gene, 281, 1–9.

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Acknowledgements

The present research was supported in part by National Institutes of Health Grants CA097318, CA88906, DK52825 and CA098172, DAMD-02-1-0041, the Samuel Waxman Cancer Research Foundation, the Lustgarten Foundation for Pancreatic Cancer Research and the Chernow Endowment. PB Fisher is the Michael and Stella Chernow Urological Cancer Research Scientist. M Sauane is the recipient of a DOD post-doctoral fellowship. We acknowledge Nikollaq Vozhilla for indispensable technical assistance and Sudhindra R Swamy of the optical microscopy facility of the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center for assistance in confocal microscopy.

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  1. Contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, 10032, NY, USA

    Moira Sauane, Rahul V Gopalkrishnan, Heng-tong Choo, Pankaj Gupta, Irina V Lebedeva & Paul B Fisher

  2. Department of Radiation Oncology, Virginia Commonwealth University, Richmond, 23298, VA, USA

    Adly Yacoub & Paul Dent

  3. Department of Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, 10032, NY, USA

    Paul B Fisher

  4. Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, 10032, NY, USA

    Paul B Fisher

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  1. Moira Sauane
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Correspondence to Paul B Fisher.

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Sauane, M., Gopalkrishnan, R., Choo, Ht. et al. Mechanistic aspects of mda-7/IL-24 cancer cell selectivity analysed via a bacterial fusion protein. Oncogene 23, 7679–7690 (2004). https://doi.org/10.1038/sj.onc.1207958

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