Acquisition of resistance to Fas-mediated apoptosis by overexpression of clusterin in human renal-cell carcinoma cells.
Recent studies have shown the antiapoptotic activity of clusterin against a wide variety of stimuli; however, the functional role of clusterin in Fas-mediated apoptosis has not been well characterized. We transfected the clusterin cDNA into human renal-cell carcinoma (RCC) ACHN cells that scarcely express clusterin protein in order to examine whether overexpression of clusterin inhibits the Fas-mediated signal pathway for apoptotic cell death. No significant difference was observed in the in vitro cell growth rates between the clusterin-transfected cell line (ACHN/CL) and the vector-only-transfected control cell line (ACHN/C), whereas the colony-forming efficiency in soft agar of ACHN/CL was significantly higher than that of ACHAN/C. The anti-Fas monoclonal antibody CH11 induced apoptosis in ACHAN/C cells in a dose-dependent manner; however, the growth-inhibitory effect of CH11 on ACHN/CL cells was markedly suppressed, with corresponding increases in p53 expression and decrease in the fraction of cells in the sub-G(1) phase of the cell cycle. Furthermore, the cytotoxic effect of CH11 on ACHN/CL cells was augmented by treatment with interferon-gamma, but a corresponding effect on ACHN/C cells was not observed. These findings suggest that overexpression of clusterin may contribute to a phenotype resistant to Fas-mediated apoptosis, and that if interferon-gamma treatment is added according to the clusterin expression level, Fas-mediated therapy could be a novel approach to RCC.
Miyake
H
H
Department of Urology, Kobe University School of Medicine, Kobe, Japan.
Hara
S
S
Zellweger
T
T
Kamidono
S
S
Gleave
M E
ME
Hara
I
I
D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000473:pathology* / Q000628:therapy; D002455:Cell Division; D051152:Clusterin; D003602:Cytotoxicity, Immunologic; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; D007376:Interleukin-2; D018832:Molecular Chaperones; D019014:fas Receptor; D007372:Interferons