Tumor Promoters - Microcystin-LR, Nodularin and TNF-alpha 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-alpha in the cells of target tissues and that TNF-alpha 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-alpha and IL-1. The carcinogenic features of TNF-alpha are described in this review, and the TNF-alpha inducing protein (Tip alpha) of elicobacter pylori genome is presented as an example of a tumor promoter of human stomach cancer development.