Induction of cyclooxygenase-2 by tumor promoters in transformed and cytochrome P450 2E1-expressing hepatocytes

Victor De Lédinghen, Hailing Liu, Fan Zhang, Chau R. Lo, Kotha Subbaramaiah, Andrew J. Dannenberg, Mark J. Czaja

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21 Scopus citations

Abstract

The induction of cyclooxygenase (COX)-2 expression has been implicated as a mechanism for the formation of non-hepatic tumors. Recent investigations have demonstrated COX-2 expression in human hepatocellular carcinomas, but little is known about the regulation of hepatocyte COX-2 expression. Employing the adult, rat hepatocyte line RALA255-10G, the effects of cellular transformation or expression of the alcohol-inducible cytochrome P450 2E1 (CYP2E1) on COX-2 expression were examined. Transformed and non-transformed hepatocytes did not express COX-2 by western and northern blot analysis. The tumor promoters phorbol 12-myristate 13-acetate (PMA) and chenodeoxycholic acid (CD) induced COX-2 protein expression in transformed, but not non-transformed cells. CYP2E1-expressing cells lacked constitutive COX-2 expression, and PMA but not CD induced COX-2 in these cells. PMA-treated transformed and CYP2E1-expressing cells expressed functional COX-2 as demonstrated by marked inductions in prostaglandin E2 synthesis. PMA-induced COX-2 expression in both transformed and CYP2E1-expressing cells resulted from an induction in COX-2 mRNA, and was dependent on extracellular signal-regulated kinase, p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase. The differential induction of COX-2 by PMA in transformed and non-transformed cells could not be explained by differences in NF-κB or C/EBPα activation. PMA did not induce COX-2 transcriptional activity as determined by transient transfections with a luciferase reporter gene driven by the COX-2 promoter. The data demonstrate that cellular transformation and CYP2E1 expression fail to lead to the induction of COX-2 expression in hepatocytes. However, these conditions do render hepatocytes susceptible to COX-2 induction from tumor promoters by post-transcriptional mechanisms.

Original languageEnglish (US)
Pages (from-to)73-79
Number of pages7
JournalCarcinogenesis
Volume23
Issue number1
StatePublished - Mar 21 2002

ASJC Scopus subject areas

  • Cancer Research

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    De Lédinghen, V., Liu, H., Zhang, F., Lo, C. R., Subbaramaiah, K., Dannenberg, A. J., & Czaja, M. J. (2002). Induction of cyclooxygenase-2 by tumor promoters in transformed and cytochrome P450 2E1-expressing hepatocytes. Carcinogenesis, 23(1), 73-79.