Tumor necrosis factor-alpha, a new tumor promoter, engendered by biochemical studies of okadaic acid.
Okadaic acid is a potent tumor promoter on mouse skin and in rat glandular stomach, and an inhibitor of PP-1 and PP-2A. How okadaic acid biochemically induces tumor promotion in these tissues was reviewed. Okadaic acid bound to a catalytic subunit of PP-1 and PP-2A and induced hyperphosphorylation of proteins, such as vimentin, cytokeratins, HSP 27, and tumor suppressor gene products. Since one of the okadaic acid class compounds, microcystin-LR, induced tumor promotion in rat liver, the okadaic acid pathway mediated through inhibition of PP-1 and PP-2A is seen to be a general biochemical process of tumor promotion in various organs. The biochemical mimicry of okadaic acid by TNF-alpha led us to find that TNF-alpha is an endogenous tumor promoter. The study of tumor promotion in two-stage carcinogenesis experiments with the okadaic acid class of compounds engendered a new tumor promoter applicable to human cancer development.
Fujiki
H
H
Saitama Cancer Center Research Institute.
Suganuma
M
M
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011955:Receptors, Drug / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D002273:Carcinogens; D004988:Ethers, Cyclic; D011955:Receptors, Drug; D014409:Tumor Necrosis Factor-alpha; C065561:okadaic acid receptor; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases