Proteasome inhibition suppresses cisplatin-dependent ERCC-1 mRNA expression in human ovarian tumor cells.
One of the major problems with ovarian cancer treatment is the clinical development of resistance to cisplatin. Considerable efforts have been directed toward the identification of biological and pharmacological agents that would reverse drug resistance to cisplatin. ALLnL is an inhibitor of the proteasome that can inhibit the ubiquitin-proteasome pathway, which plays an essential role in many processes in cell life. We have recently shown that ALLnL, at concentrations that do not appear harmful, has significantly enhanced DNA platination and decreased DNA repair of cisplatin-DNA adducts in human A2780/CP70 ovarian carcinoma cells. These activities of proteasome inhibition were also associated with substantially increased cisplatin toxicity in these cells. In this communication, we demonstrate that treatment of A2780/CP70 cells with ALLnL blocks cisplatin-induced ERCC-1 mRNA expression in a concentration- and time-dependent manner, as measured by Northern blot analysis. In addition, we showed that the cisplatin-dependent increase in steady-state levels of ERCC-1 mRNA was prevented by pretreatment with lactacystin, a potent and specific inhibitor of proteasome. These results suggest that the effect of proteasome inhibition on cisplatin cytotoxicity, DNA platination, and DNA repair of cisplatin adducts in ovarian cancer cells may be through down-regulating ERCC-1 expression.
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Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. qli001@umaryland.edu
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D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D003546:Cysteine Endopeptidases; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases; D005260:Female; D006801:Humans; D007769:Lactams; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; D007769:Lactams; D009097:Multienzyme Complexes; D011506:Proteins; D012333:RNA, Messenger; C067713:lactacystin; C071447:ERCC1 protein, human; D004720:Endonucleases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin; D000111:Acetylcysteine