Journal Article

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 and Mark J. Czaja

in Carcinogenesis

Volume 23, issue 1, pages 73-79
Published in print January 2002 | ISSN: 0143-3334
Published online January 2002 | e-ISSN: 1460-2180 | DOI:
Induction of cyclooxygenase-2 by tumor promoters in transformed and cytochrome P450 2E1-expressing hepatocytes

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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.

Keywords: ALD, alcoholic liver disease; CD, chenodeoxycholic acid; COX, cyclooxygenase; CYP2E1, cytochrome P450 2E1; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal-regulated kinase; FBS, fetal bovine serum; HCC, hepatocellular carcinoma; MAPK, mitogen-activated protein kinase; PGE2, prostaglandin E2; PI 3-K, phosphatidylinositol 3-kinase; PMA, phorbol 12-myristate 13-acetate; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α

Journal Article.  5264 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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