TAUTOMYCIN - AN INHIBITOR OF PROTEIN PHOSPHATASE-1 AND PHOSPHSTASE-2ABUT NOT A TUMOR PROMOTER ON MOUSE SKIN AND IN RAT GLANDULAR STOMACH

Tautomycin isolated from Streptomyces spiroverticillatus is an inhibit or of protein phosphatases 1 and 2A. Tautomycin induced hyperphosphory lation of cytokeratin peptides in human keratinocytes (PHK 16-I cells) 30 times less strongly than did okadaic acid. Repeated applications o f tautomycin (30 mu g, 40 nmol/application) did not induce tumor promo tion in a two-stage carcinogenesis experiment on mouse skin initiated with 7,12-dimethylbenz[a]anthracene, whereas okadaic acid (1 mu g, 1.2 nmol/application) application) as a control induced tumor promotion s trongly. As for mucosa of rat glandular stomach, tautomycin induced or nithine decarboxylase 4 h after intubation into the stomach. The tumor -promoting activity of tautomycin was next studied in the glandular st omach initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Admi nistration of tautomycin in the diet (1 mg rat(-1) day(-1)), from week 9 to week 52 of the experiment, inhibited rather than enhanced tumor development in the glandular stomach initiated with MNNG. The percenta ges of tumor-bearing rats of the groups treated with MNNG plus tautomy cin, MNNG alone, and tautomycin alone were 20.0%, 40.6%, and 0% respec tively in week 52. The reason for the absence of tumor-promoting activ ity of tautomycin was studied in relation to tumor necrosis factor alp ha (TNF alpha), an endogenous tumor promoter. We found that tautomycin neither enhanced TNF alpha mRNA expression in mouse skin nor induced TNF alpha release in a human stomach cancer cell line (KATO III cells) , whereas okadaic acid did both. These results indicate that not all i nhibitors of protein phosphatases are tumor promoters, and suggest tha t tumor promotion of the okadaic acid class of compounds is mediated b y TNF alpha.