Modulation of excision repair cross complementation group 1 (ERCC-1) mRNA expression by pharmacological agents in human ovarian carcinoma cells

Excision repair cross complementation group 1 (ERCC-1) is a DNA repair gene that is essential for life, and it appears to be a marker gene for nucleot ide excision repair activity. Overexpression of ERCC-1 during cisplatin bas ed chemotherapy is associated with clinical and cellular drug resistance. W e therefore began to assess the influence of various pharmacological agents on the induction of ERCC-1 mRNA in A2780/CP70 human ovarian carcinoma cell s. Cisplatin exposure in culture resulted in a 4- to 6-fold induction for t he steady-state level of ERCC-1 mRNA in A2780/CP70 cells. ERCC-1 mRNA induc tion was concentration and time dependent. Cyclosporin A and herbimycin A, which suppress c-fos and c-jun gene expressions, respectively, blocked the cisplatin-induced increase in ERCC-I mRNA. This effect of cyclosporin A or herbimycin A on the down-regulation of ERCC-I correlates with enhanced cyto toxicity of cisplatin in this system. The products of c-Jos and c-jun are c omponents of the transcription factor AP-1 (activator protein 1). 12-O- Tet radecanoylphorbal 13 acetate (TPA), a known AP-1 agonist, induced ERCC-1 mR NA to the same extent as cisplatin, but did not synergize with cisplatin in this regard. The TPA effect was biphasic, with an initial increase during the first 1-6 hr, followed by decreasing mRNA levels at 24-72 hr. These dat a suggest that the effects of these pharmacological agents on ERCC-I gene e xpression may be mediated through the modulation of AP-1 activities. (C) 19 99 Elsevier Science Inc.