Effect of interleukin-1 alpha and tumour necrosis factor-alpha on cisplatin-induced ERCC-1 mRNA expression in a human ovarian carcinoma cell line.
Enhanced expression of the human excision repair enzyme ERCC-1 is associated with cellular and clinical resistance to cisplatin in human ovarian cancer. High levels of expression of ERCC-1 appear to be associated with increased activity of the nucleotide excision repair pathway. We therefore began to examine the effect of some cisplatin resistance modulators on cisplatin-induced ERCC-1 mRNA expression in the human ovarian carcinoma cell line, A2780/CP70. Cisplatin exposure to A2780/CP70 cells in culture resulted in a four- to five-fold induction for steady-state ERCC-1 mRNA, that was dose- and time-dependent. The biological agents interleukin (IL)-1 alpha and tumour necrosis factor (TNF)-alpha have been shown to enhance cisplatin cytotoxicity in vitro. IL-1 alpha inhibited cisplatin induction of ERCC-1 mRNA levels in our system. The effect of IL-1 alpha was sequence dependent, in that the maximum inhibitory effect was observed with 24-hour pretreatment with IL-1 alpha. By contrast, TNF-alpha had little effect on ERCC-1 mRNA induction by cisplatin. Low-temperature hyperthermia (42 degrees C) almost completely suppressed ERCC-1 mRNA induction in these cells. These findings suggest that the enhancement effect of some agents on cisplatin sensitivity in ovarian tumour cells may be through downregulating ERCC-1 expression.
Developmental Therapeutics Department, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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Li
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Bostick-Bruton
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Reed
D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D007700:Kinetics; D010051:Ovarian Neoplasms; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin