A member of the GAGE family of tumor antigens is an anti-apoptotic gene that confers resistance to Fas/CD95/APO-1, Interferon-gamma, taxol and gamma-irradiation.
Attractive targets for cancer therapy are gene products whose inactivation is not detrimental in essential tissues. The GAGE family of Cancer/Testis Antigens is a group of appealing candidates for cancer therapy since they are expressed in a wide variety of human tumors and are silent in most adult tissues, with the exception of testis. Interestingly, expression of GAGE has been associated with poor prognosis in some cancers. Nevertheless, no function has been reported for any of the GAGE family members. Here we describe for the first time an anti-apoptotic activity exerted by GAGE. We have cloned GAGE-7C from HeLa cells and showed that it renders transfected cells resistant to apoptosis induced by Interferon-gamma (IFN-gamma) or by the death receptor Fas/CD95/APO-1. Similarly, transfection of GAGE-7/7B also confers resistance to Fas induced apoptosis. In the Fas pathway, the anti-apoptotic activity of GAGE-7C maps downstream of caspase-8 activation and upstream of poly (ADP-ribose) polymerase (PARP) cleavage. Furthermore, GAGE-7C renders the cells resistant to the therapeutic agents Taxol and gamma-irradiation. Following the various apoptotic stimuli, the surviving GAGE-7C transfectants actively proliferate and exhibit enhanced long term survival in colony formation assays. Overall, our data establishes a functional link between GAGE-7C and two aspects of human tumor progression; namely, resistance to Fas induced apoptosis and to chemo- and radio-therapy.
Cilensek
Zoran M
ZM
Department of Molecular Genetics, University of Illinois at Chicago, 60607, USA.
Yehiely
Fruma
F
Kular
Rupinder K
RK
Deiss
Louis P
LP
D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005720:Gamma Rays; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D019169:Jurkat Cells; D009363:Neoplasm Proteins; D017239:Paclitaxel / Q000494:pharmacology*; D010957:Plasmids / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D019014:fas Receptor / Q000494:pharmacology*
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; C113434:GAGE7 protein, human; D009363:Neoplasm Proteins; D019014:fas Receptor; D007371:Interferon-gamma; D011065:Poly(ADP-ribose) Polymerases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D017239:Paclitaxel