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Cholesterol Sulfate, a Second Messenger for the Isoform of Protein Kinase C, Inhibits Promotional Phase in Mouse Skin Carcinogenesis¹

Department of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo 108, Japan

Cholesterol sulfate is a second messenger for the isoform of protein kinase C mediating squamous differentiation. We found that cholesterol sulfate inhibited the promotional phase of skin carcinogenesis in female CD-1 mice, which was initiated by 100 µg 7,12-dimethylbenz[a]-anthracene and promoted by a single application of 10 µg 12-O-tetradecanoylphorbol-13-acetate, followed by repeated applications of 10 µg mezerein once a week for 19 weeks. Cholesterol sulfate, when applied topically at a dose of 400 µg (820 µmol) 10 min before treatment with the promoters, markedly suppressed tumor formation, resulting in decrease of 56% in the incidence of tumor-bearing mice, 81% in the number of tumors/mouse, and 60% in the size of tumors at 20 weeks of the promotion. This inhibition was not due to elimination of the initiated cells. Treatment with the parental cholesterol at a dose of 320 µg (820 µmol), which does not activate the isoform, did not inhibit tumor promotion. Repeated treatment with cholesterol sulfate induced scaling of skin at the site of application. Cholesterol sulfate, unlike most inhibitors of tumor promotion, did not inhibit induction of ornithine decarboxylase and hyperplasia in mouse epidermis caused by topical treatment with 12-O-tetradecanoylphorbol-13-acetate. These findings suggest that cholesterol sulfate inhibits tumor promotion by stimulating a differentiation pathway mediated by the isoform of protein kinase C.

¹ This research was supported by a Grant-in-Aid for Special Project for Cancer Research from the Ministry of Education, Science and Culture of Japan.

² To whom requests for reprints should be addressed, at Department of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo 108, Japan. Phone: +81-3-5449-5255; Fax: +81-3-5449-5414.

Received 3/27/95. Accepted 8/25/95.

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