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/Fas-ligand family play a predominant role in apoptosis induction in tumor cells, and are critical in cancer therapy. In this study we used the human breast-carcinoma cell line MCF7, its derivatives MCF7Adr (resistant to adriamycin) and R-A1 (resistant to TNF), to determine the impact of acquired drug and cytokine resistance on susceptibility to Fas-induced cytotoxicity and Fas-antigen expression. While MCF7 and R-A1 cells were killed by anti-Fas in the presence of IFN-gamma, MCF7Adr was found to be resistant to Fas-mediated apoptosis. This resistance was correlated with a loss of surface Fas-protein expression. Fas-gene transfer in MCF7Adr resulted in high sensitivity to Fas-mediated cytotoxicity, indicating that the Fas signalling pathway is virtually intact in this cell line. Over-expression of the MDR1 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 not directly involved in the loss of Fas expression, contrary to what has been observed by others in T-cell lines. Furthermore, the down-regulation of Fas expression and subsequent resistance to anti-Fas were observed in drug-resistant human ovarian-carcinoma IGR-OV1/VCR cells and leukemic lymphoblast CEM/VLB cells, suggesting that the alteration of Fas expression following drug-resistance selection is not restricted to one cell type.
Cai
Z
Z
INSERM CJF 94-11 Cytokines et Immunité Antitumorale, Institut Gustave Roussy, Villejuif, France.
Stancou
R
R
Körner
M
M
Chouaib
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics* / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D014750:Vincristine; D014747:Vinblastine; D004317:Doxorubicin; D007371:Interferon-gamma