Unique features of the okadaic acid activity class of tumor promoters

Following the first report of tumor promotion by okadaic acid in 1988, we f urther identified additional tumor promoters of the okadaic acid activity c lass, such as calyculin A and microcystin-LR. However, tautomycin, which is also an inhibitor of protein phosphatases-l and -2A (PP-1 and PP-2A), as a re okadaic acid, calyculin A and microcystin-LR, is not a tumor promoter on mouse skin or in rat glandular stomach. This paper presents unique feature s of the okadaic acid activity class of tumor promoters with regards to thr ee significant findings: 1) the okadaic acid pathway, mediated through inhi bition of PP-I and PP-2A, is a general tumor promotion pathway in various o rgans; 2) simultaneous treatment of okadaic acid with teleocidin, one of th e 12-O-tetradecanoylphorbol-13-acetate (TPA) activity type of tumor promote rs, did not show any synergistic effects on tumor promotion;and 3) two diff erent types of tumor promoters, okadaic acid and TPA, commonly induced tumo r necrosis factor-alpha (TNF-alpha) gene expression on mouse skin. The resu lts also strongly suggest that TNF-alpha, now known to be an endogenous tum or promoter and a mediator of cancer development, plays an important role i n tumor promotion and progression in humans. In the light of this, we discu ss a practical method of screening for chemical tumor promoters based on th eir induction of TNF-alpha release from HL-60 cells.