Cisplatin induction of ERCC-1 mRNA expression in A2780/CP70 human ovarian cancer cells.

Abstract ERCC-1 is a critical gene within the nucleotide excision repair pathway, and cells without a functionalERCC-1 do not perform cisplatin-DNA adduct repair. We therefore investigated the cisplatin effect on ERCC-1mRNA expression in vitro. In response to a 1-h cisplatin exposure, A2780/CP70 human ovarian cancer cells showed a 6-fold increase in steady-state level of ERCC-1 mRNA. This rise was attributable to increased transcription as measured by nuclear run-on assays and a 60% increase in ERCC-1mRNA half-life. The increase in ERCC-1 mRNA was preceded by a 4–5-fold rise in mRNA expressions ofc-fos and c-jun, a 14-fold increase in c-Jun protein phosphorylation, and an increase in in vitronuclear extract binding activity to the AP-1-like site ofERCC-1. These data suggest that the induction ofERCC-1 expression in A2780/CP70 cells exposed to cisplatin results from two major factors: (a) an increase in the expression of transactivating factors that bind the AP-1-like site in the 5′-flanking region of ERCC-1 and (b) an increase in the level of c-Jun phosphorylation that enhances its transactivation property.