Unique features of the okadaic acid activity class of tumor promoters

Following the first report of tumor promotion by okadaic acid in 1988, we further identified additional tumor promoters of the okadaic acid activity class, 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 are okadaic acid, calyculin A and microcystin-LR, is not a tumor promoter on mouse skin or in rat glandular stomach. This paper presents unique features of the okadaic acid activity class of tumor promoters with regards to three significant findings: 1) the okadaic acid pathway, mediated through inhibition of PP-I and PP-2A, is a general tumor promotion pathway in various organs; 2) simultaneous treatment of okadaic acid with teleocidin, one of the 12-O-tetradecanoylphorbol-13-acetate (TPA) activity type of tumor promoters, did not show any synergistic effects on tumor promotion;and 3) two different types of tumor promoters, okadaic acid and TPA, commonly induced tumor necrosis factor-alpha (TNF-alpha) gene expression on mouse skin. The results also strongly suggest that TNF-alpha, now known to be an endogenous tumor promoter and a mediator of cancer development, plays an important role in tumor promotion and progression in humans. In the light of this, we discuss a practical method of screening for chemical tumor promoters based on their induction of TNF-alpha release from HL-60 cells.