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

Biochem Pharmacol. 1999 Feb 15;57(4):347-53. doi: 10.1016/s0006-2952(98)00291-3.

Abstract

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 nucleotide excision repair activity. Overexpression of ERCC-1 during cisplatin-based chemotherapy is associated with clinical and cellular drug resistance. We therefore began to assess the influence of various pharmacological agents on the induction of ERCC-1 mRNA in A2780/CP70 human ovarian carcinoma cells. Cisplatin exposure in culture resulted in a 4- to 6-fold induction for the steady-state level of ERCC-1 mRNA in A2780/CP70 cells. ERCC-1 mRNA induction 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-1 mRNA. This effect of cyclosporin A or herbimycin A on the down-regulation of ERCC-1 correlates with enhanced cytotoxicity of cisplatin in this system. The products of c-fos and c-jun are components of the transcription factor AP-1 (activator protein 1). 12-O-Tetradecanoylphorbol 13-acetate (TPA), a known AP-1 agonist, induced ERCC-1 mRNA 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 data suggest that the effects of these pharmacological agents on ERCC-1 gene expression may be mediated through the modulation of AP-1 activities.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Benzoquinones
  • Cisplatin / pharmacology*
  • Cyclosporine / pharmacology
  • DNA Repair*
  • DNA-Binding Proteins*
  • Endonucleases*
  • Gene Expression Regulation / drug effects*
  • Humans
  • Lactams, Macrocyclic
  • Protein Biosynthesis
  • Proteins / genetics*
  • Quinones / pharmacology
  • RNA, Messenger / biosynthesis
  • Rifabutin / analogs & derivatives
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tumor Cells, Cultured

Substances

  • Benzoquinones
  • DNA-Binding Proteins
  • Lactams, Macrocyclic
  • Proteins
  • Quinones
  • RNA, Messenger
  • Rifabutin
  • herbimycin
  • Cyclosporine
  • ERCC1 protein, human
  • Endonucleases
  • Tetradecanoylphorbol Acetate
  • Cisplatin