Tautomycin: An inhibitor of protein phosphatases 1 and 2A but not a tumor promoter on mouse skin and in rat glandular stomach

Publisher Website
Google Scholar
Abstract
Tautomycin isolated fromStreptomyces spiroverticillatus is an inhibitor of protein phosphatases 1 and 2A. Tautomycin induced hyperphosphorylation of cytokeratin peptides in human keratinocytes (PHK 16-I cells) 30 times less strongly than did okadaic acid. Repeated applications of tautomycin (30 μg, 40 nmol/application) did not induce tumor promotion in a two-stage carcinogenesis experiment on mouse skin initiated with 7,12-dimethylbenz[a]anthracene, whereas okadaic acid (1 μg, 1.2 nmol/application) as a control induced tumor promotion strongly. As for mucosa or rat glandular stomach, tautomycin induced ornithine decarboxylase 4 h after intubation into the stomach. The tumor-promoting activity of tautomycin was next studied in the glandular stomach initiated withN-methyl-N ′-nitro-N-nitrosoguanidine (MNNG). Administration 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 percentages of tumor-bearing rats of the groups treated with MNNG plus tautomycin, MNNG alone, and tautomycin alone were 20.0%, 40.6%, and 0% respectively in week 52. The reason for the absence of tumor-promoting activity of tautomycin was studied in relation to tumor necrosis factor α (TNFα), an endogenous tumor promoter. We found that tautomycin neither enhanced TNFα mRNA expression in mouse skin nor induced TNFα release in a human stomach cancer cell line (KATO III cells), whereas okadaic acid did both. These results indicate that not all inhibitors of protein phosphatases are tumor promoters, and suggest that tumor promotion of the okadaic acid class of compounds is mediated by TNFα.