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Vol. 273, Issue 4, 2424-2428, January 23, 1998
From the ¶ Departments of Medicine and Surgery and the
§ Department of Cardiothoracic Surgery, Bile acids, endogenous promoters of
gastrointestinal cancer, activate protein kinase C (PKC) and the
activator protein-1 (AP-1) transcription factor. Because other
activators of PKC and AP-1 induce cyclooxygenase-2 (COX-2), we
determined the effects of bile acids on the expression of COX-2 in
human esophageal adenocarcinoma cells. Treatment with the dihydroxy
bile acids chenodeoxycholate and deoxycholate resulted in an ~10-fold
increase in the production of prostaglandin E2
(PGE2). Enhanced synthesis of PGE2 was
associated with a marked increase in the levels of COX-2 mRNA and
protein, with maximal effects at 8-12 and 12-24 h, respectively. In
contrast, neither cholic acid nor conjugated bile acids affected the
levels of COX-2 or the synthesis of PGE2. Nuclear run-off
assays and transient transfections with a human COX-2
promoter construct showed that induction of COX-2 mRNA by
chenodeoxycholate and deoxycholate was due to increased transcription.
Bile acid-mediated induction of COX-2 was blocked by inhibitors of PKC
activity, including calphostin C and staurosporine. Treatment with bile
acid enhanced the phosphorylation of c-Jun and increased binding of
AP-1 to DNA. These data are important because dihydroxy bile
acid-mediated induction of COX-2 may explain, at least in part, the
tumor-promoting effects of bile acids.
Dihydroxy Bile Acids Activate the Transcription of
Cyclooxygenase-2
§,¶,§, and¶
Strang Cancer
Prevention Center, New York, New York 10021
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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P. Michaluart, J. L. Masferrer, A. M. Carothers, K. Subbaramaiah, B. S. Zweifel, C. Koboldt, J. R. Mestre, D. Grunberger, P. G. Sacks, T. Tanabe, et al. Inhibitory Effects of Caffeic Acid Phenethyl Ester on the Activity and Expression of Cyclooxygenase-2 in Human Oral Epithelial Cells and in a Rat Model of Inflammation Cancer Res., May 1, 1999; 59(10): 2347 - 2352. [Abstract] [Full Text] [PDF]
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K. Subbaramaiah, N. Altorki, W. J. Chung, J. R. Mestre, A. Sampat, and A. J. Dannenberg Inhibition of Cyclooxygenase-2 Gene Expression by p53 J. Biol. Chem., April 16, 1999; 274(16): 10911 - 10915. [Abstract] [Full Text] [PDF]
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O. N. Tucker, A. J. Dannenberg, E. K. Yang, F. Zhang, L. Teng, J. M. Daly, R. A. Soslow, J. L. Masferrer, B. M. Woerner, A. T. Koki, et al. Cyclooxygenase-2 Expression Is Up-Regulated in Human Pancreatic Cancer Cancer Res., March 1, 1999; 59(5): 987 - 990. [Abstract] [Full Text] [PDF]
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