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Calyculin A, an Inhibitor of Protein Phosphatases, a Potent Tumor Promoter on CD-1 Mouse Skin¹

Cancer Prevention Division, National Cancer Center Research Institute, Tokyo 104 [M. S., H. F., H. F-S., S. Y.]; Laboratory of Molecular Oncology, Kanagawa Cancer Center Research Institute, Kanagawa 241 [S. Y.]; Faculty of Agriculture, University of Tokyo, Tokyo 113 [Y. K., N. F.]; and National Cancer Center, Tokyo 104 [T. S.], Japan

Calyculin A, isolated from a marine sponge, has a novel spiro ketal skeleton. Structurally unrelated to okadaic acid, calyculin A bound to the okadaic acid receptors in particulate and soluble fractions of mouse skin. The biochemical and tumor-promoting activities of calyculin A were studied with those of okadaic acid. Calyculin A inhibited the activity of protein phosphatases, which serve as the okadaic acid receptors. The effective dose of calyculin A for 50% inhibition was 0.3 nM, similar to that of okadaic acid. Like okadaic acid, calyculin A induced ornithine decarboxylase in mouse skin and hyperphosphorylation of a M_r 60,000 protein in human papilloma virus type 16-transformed human keratinocytes. A two-stage carcinogenesis experiment on mouse skin, initiated by 100 µg (390 nmol) of 7,12-dimethylbenz(a)anthracene and followed by 1 µg (1.0 nmol) of calyculin A, revealed that calyculin A is an additional member of the okadaic acid class of tumor promoters. The percentages of tumor-bearing mice in the groups treated with DMBA plus calyculin A, and with DMBA followed by 1 µg (1.2 nmol) of okadaic acid were 86.7 and 80.0%, respectively, in week 30. The mechanisms of action of calyculin A and okadaic acid, in addition to dinophysistoxin-1 (35-methylokadaic acid), are discussed. Calyculin A is the first tumor promoter to be screened by the okadaic acid receptor binding test.

¹ This work was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science and Culture and the Ministry of Health and Welfare, for a Comprehensive 10-Year Strategy for Cancer Control, Japan, and the Princess Takamatsu Cancer Research Fund.

² To whom requests for reprints should be addressed.

Received 10/ 3/89. Revised 2/12/90.

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