Tumor promoters--microcystin-LR, nodularin and TNF-α and human cancer development.
Microcystin-LR and nodularin, along with okadaic acid, are potent inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A). The mechanisms of action of microcystin-LR and nodularin in the liver and that of okadaic acid, a potent tumor promoter on mouse skin, have attracted the attention of the scientists. This paper reviews several topics: new inhibitors of PP1 and PP2A with new chemical structures, structure-function relationships for both receptor binding and inhibition of protein phosphatases, the crystal structure of PP1 or PP2A-toxin complex, induction of gene expression and apoptosis. These subjects were studied by using in vitro and in vivo experimental systems. Two-stage carcinogenesis experiments with microcystin-LR and nodularin for the first time demonstrated that microcystin-LR is a new tumor promoter in rat liver initiated with diethylnitrosamine (DEN), and that nodularin is a potent tumor promoter associated with weak initiating activity in rat liver initiated with DEN. A working group of WHO (IARC) concluded that microcystin-LR is "possibly carcinogenic to humans" and that nodularin is "not classifiable as to carcinogenicity". Our studies revealed that chemical tumor promoters are inducers of TNF-α in the cells of target tissues and that TNF-α is an endogenous tumor promoter. This advance in carcinogenesis made it possible to look for the link between chemical tumor promoters and endogenous tumor promoters, such as TNF-α and IL-1. The carcinogenic features of TNF-α are described in this review, and the TNF-α inducing protein (Tipα) of Helicobacter pylori genome is presented as an example of a tumor promoter of human stomach cancer development.
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Japan. hfujiki@ph.bunri-u.ac.jp
Hirota
H
Fujiki
Masami
M
Suganuma
D000818:Animals; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D006801:Humans; D008387:Marine Toxins; D052998:Microcystins / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D019319:Okadaic Acid / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D002273:Carcinogens; D008387:Marine Toxins; D052998:Microcystins; D010456:Peptides, Cyclic; D014409:Tumor Necrosis Factor-alpha; C063998:nodularin; D019319:Okadaic Acid; D017027:Protein Tyrosine Phosphatases; C057862:cyanoginosin LR