The role of c-Jun in the AP-1 activation induced by naturally occurring isothiocyanates.
Despite strong evidence that isothiocyanates (ITCs) inhibit cancer development, there are also reports that some of them induce or promote carcinogenesis. The molecular basis of the latter is largely unknown. We report here that all three ITCs that caused urinary bladder cancer in rats, including allyl ITC, benzyl ITC, and phenethyl ITC, increased the transactivation of activator protein 1 (AP-1) and AP-1 DNA binding in human bladder cancer UM-UC-3 cells. Amongst all Fos and Jun family members examined, only were the levels of c-Jun and Fra-2 consistently elevated by the ITCs. However, whereas c-Jun was identified as the predominant component in the AP-1 DNA binding complex, Fra-2 was not detected, suggesting that c-Jun may be mainly responsible for ITC-induced AP-1 activation. c-Jun was also induced by the ITCs in other bladder cancer cell lines (both human and rat) and by their N-acetylcysteine derivatives--their main urinary metabolites. c-Jun induction by the ITCs appears to involve both transcriptional activation and protein phosphorylation; the latter resulted from activation of c-Jun N-terminal kinase by the ITCs. Because c-Jun has been implicated in cancer development, including human bladder cancer, our data suggest that c-Jun activation may play an important role in ITC-induced bladder carcinogenesis.
Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
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D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D010766:Phosphorylation; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D004273:DNA, Neoplasm; D017879:Isothiocyanates; D018808:Transcription Factor AP-1; C058305:phenethyl isothiocyanate; C031403:benzyl isothiocyanate; C004471:allyl isothiocyanate; D008156:Luciferases