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Mechanism of Action of Chemoprotective Ursodeoxycholate in the Azoxymethane Model of Rat Colonic Carcinogenesis: Potential Roles of Protein Kinase C-, -ß_II, and -¹

Department of Medicine, University of Chicago, Chicago, Illinois 60637 [R. K. W., B. P. F., S. H., H. K. R., S. K., B. A. S-S., M. D. S., T. A. B., M. B.], and Department of Medicine, University of Arizona, Tucson, Arizona 85721 [D. L. E.]

Several lines of evidence from our laboratory and others indicate that epigenetic alterations in protein kinase C (PKC) are involved in colonic carcinogenesis in both man and experimental animals. Furthermore, bile salts, known activators of PKC, have also been implicated in colonic tumor development. Recently, however, our laboratory has demonstrated that, whereas dietary cholic acid increased the occurrence of azoxymethane (AOM)-induced rat colonic tumors, ursodeoxycholic acid was associated with a significant protective effect. In the present studies, we therefore examined changes in PKC isoforms that accompanied AOM-induced tumor formation and investigated whether the chemopromotional and/or chemopreventional actions of these supplemental dietary bile salts involved changes in specific isoforms of PKC. Rats treated with vehicle (saline) or AOM and maintained on bile salt unsupplemented or supplemented diets were used to isolate control colonocytes and carcinogen-induced tumors, which were then subjected to subcellular fractionation. The homogenates and subcellular fractions were then probed for individual PKC isoforms by quantitative Western blotting using isoform-specific antibodies. Normal rat colonocytes expressed PKC-, -ß_II, -, -, and -. AOM, in unsupplemented or cholate-supplemented groups, caused significant down-regulation of PKC-, - and - and up-regulation of PKC-ß_II, while increasing particulate PKC-, -ß_II, and - in carcinogen-induced tumors compared to normal colonocytes. Dietary supplementation with ursodeoxycholic acid, in marked contrast to these groups, prevented the changes in the subcellular distributions of PKC-, -ß_II, and -, and preserved the expression of PKC- in AOM-induced tumors. These studies suggest that changes in specific isoforms of PKC (particularly, PKC-, -ß_II, -, and/or -) are involved in colonic malignant transformation in the AOM model but do not account for the chemopromotional actions of cholic acid in this model. Furthermore, the ability of ursodeoxycholic acid to block AOM-induced increases in particulate PKC-, -ß_II, and -, and/or inhibit down-regulation of PKC-, may contribute to the chemopreventive effects of this bile acid.

¹ The study was funded in part by Ciba-Geigy, Inc.; the Samuel Freedman Laboratories for Cancer Research; United States Public Health Service Grants CA 36745 (T. A. B) and CA 41108 (D. L. E.), awarded by the National Cancer Institute; and United States Public Health Service Grant DK 42086 (University of Chicago Digestive Disease Core Research Center) and DK02022 (M. B.).

² Recipient of a MERIT Award from the National Cancer Institute.

³ To whom requests for reprints should be addressed, at Department of Medicine, MC 4076, University of Chicago Hospitals and Clinics, 5841 South Maryland Avenue, Chicago, IL 60637.

Received 6/26/95. Accepted 9/19/95.

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