CHOLESTEROL SULFATE, A 2ND-MESSENGER FOR THE ETA-ISOFORM OF PROTEIN-KINASE-C, INHIBITS PROMOTIONAL PHASE IN MOUSE SKIN CARCINOGENESIS

Cholesterol sulfate is a second messenger for the eta isoform of prote in kinase C mediating squamous differentiation. We found that choleste rol sulfate inhibited the promotional phase of skin carcinogenesis in female CD-1 mice, which was initiated by 100 mu g 7,12-dimethylbenz[a] -anthracene and promoted by a single application of 10 mu g 12-O-tetra decanoylphorbol-13-acetate, followed by repeated applications of 10 mu g mezerein once a week for 19 weeks. Cholesterol sulfate, when applie d topically at a dose of 400 mu g (820 mu mol) 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 nu mber 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 initiate d cells. Treatment with the parental cholesterol at a dose of 320 mu g (820 mu mol), which does not activate the eta isoform, did not inhibi t tumor promotion. Repeated treatment with cholesterol sulfate induced scaling of skin at the site of application. Cholesterol sulfate, unli ke most inhibitors of tumor promotion, did not inhibit induction of or nithine decarboxylase and hyperplasia in mouse epidermis caused by top ical treatment with 12-O-tetradecanoylphorbol-13-acetate. These findin gs suggest that cholesterol sulfate inhibits tumor promotion by stimul ating a differentiation pathway mediated by the eta isoform of protein kinase C.