TUMOR PROMOTION BY INHIBITORS OF PROTEIN PHOSPHATASE-1 AND PHOSPHATASE-2A - THE OKADAIC ACID CLASS OF COMPOUNDS

Tumor promotion by the okadaic acid class of compounds binds to the okadaic acid receptors protein phosphatases 1 and 2A (PP-1 and PP-2A), which inhibit their activities. It results in an increase of phosphorylation of proteins in the cells. This chapter reviews the okadaic acid class of tumor promoters and discusses the significance of inhibition of PP-1 and PP-2A—the okadaic acid pathway—in the study of tumor promotion. Two-stage carcinogenesis experiments with the okadaic acid class of compounds established a general mechanism of tumor promotion for various organs. Okadaic acid was subjected to screening system for 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, which consist of three successive tests. Okadaic acid responded differently from TPA in the three tests. Thirty okadaic acid class compounds include four structurally different types—namely, okadaic acid, calyculin, microcystin, and tautomycin. The tumor promotion on mouse skin, rat glandular stomach, and the treatment of okadaic acid with teleocidin or TPA are also discussed in the chapter. Okadaic acid and teleocidin showed about the same potencies for production of papillomas and carcinomas during tumor promotion. The structure, distribution, gene expression, and biochemical effects of okadaic acid class compounds are also summarized. © 1993, Academic Press Inc.