IMPAIRMENT OF FAS-ANTIGEN EXPRESSION IN ADRIAMYCIN-RESISTANT BUT NOT TNF-RESISTANT MCF7 TUMOR-CELLS

Anti-cancer drugs and cytotoxic cytokines such as members of the TNF/F as-ligand family play a predominant role in apoptosis induction in tum or cells, and are critical in cancer therapy. In this study we used th e human breast-carcinoma cell line MCF7, its derivatives MCF7Adr (resi stant to adriamycin) and R-AI (resistant to TNF), to determine the imp act of acquired drug and cytokine resistance on susceptibility to Far- induced cytotoxicity and Fas-antigen expression. While MCF7 and R-AI c ells were killed by anti-Fas in the presence of IFN-gamma, MCF7Adr was found to be resistant to Far-mediated apoptosis. This resistance was correlated with a loss of surface Fas-protein expression. Fas-gene tra nsfer in MCF7Adr resulted in high sensitivity to Fas-mediated cytotoxi city, indicating that the Fas signalling pathway is virtually intact i n this cell line. Over-expression of the MDR I gene in MCF7 following gene transfer did not affect Fas expression and anti-Fas sensitivity, suggesting that the P-gp-mediated multidrug-resistance phenotype is no t directly involved in the loss of Fas expression, contrary to what ha s been observed by others in T-cell lines. Furthermore, the downregula tion of Fas expression and subsequent resistance to anti-Fas were obse rved in drug-resistant human ovarian-carcinoma IGR-OVI/VCR cells and l eukemic lymphoblast GEM/VLB cells, suggesting that the alteration of F as expression following drug-resistance selection is not restricted to one cell type. (C) 1996 Wiley-Liss, Inc.