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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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 - 2002

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Cytochrome P-450 CYP2E1
Cyclooxygenase 2
Carcinogens
Hepatocytes
Acetates
Chenodeoxycholic Acid
Phosphatidylinositol 3-Kinase
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases

ASJC Scopus subject areas

  • Cancer Research

Cite this

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.

Induction of cyclooxygenase-2 by tumor promoters in transformed and cytochrome P450 2E1-expressing hepatocytes. / De Lédinghen, Victor; Liu, Hailing; Zhang, Fan; Lo, Chau R.; Subbaramaiah, Kotha; Dannenberg, Andrew J.; Czaja, Mark J.

In: Carcinogenesis, Vol. 23, No. 1, 2002, p. 73-79.

Research output: Contribution to journalArticle

De Lédinghen, V, Liu, H, Zhang, F, Lo, CR, Subbaramaiah, K, Dannenberg, AJ & Czaja, MJ 2002, 'Induction of cyclooxygenase-2 by tumor promoters in transformed and cytochrome P450 2E1-expressing hepatocytes', Carcinogenesis, vol. 23, no. 1, pp. 73-79.
De Lédinghen V, Liu H, Zhang F, Lo CR, Subbaramaiah K, Dannenberg AJ et al. Induction of cyclooxygenase-2 by tumor promoters in transformed and cytochrome P450 2E1-expressing hepatocytes. Carcinogenesis. 2002;23(1):73-79.
De Lédinghen, Victor ; Liu, Hailing ; Zhang, Fan ; Lo, Chau R. ; Subbaramaiah, Kotha ; Dannenberg, Andrew J. ; Czaja, Mark J. / Induction of cyclooxygenase-2 by tumor promoters in transformed and cytochrome P450 2E1-expressing hepatocytes. In: Carcinogenesis. 2002 ; Vol. 23, No. 1. pp. 73-79.
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