THE ANTITUMOR DRUG FOSTRIECIN INDUCES VIMENTIN HYPERPHOSPHORYLATION AND INTERMEDIATE FILAMENT REORGANIZATION

Fostriecin is an antitumor drug in phase I clinical trials, We have re cently shown that it is a potent inhibitor of protein phosphatases 1 a nd 2A in vitro, a property not previously described for an antitumor d rug, We have investigated its effects on protein phosphorylation in ba by hamster kidney cells, Fostriecin strongly stimulated the phosphoryl ation of a single protein, which we identified as the intermediate fil ament vimentin, Fostriecin also caused rounding of the cells and a reo rganization of the vimentin filaments. These effects are similar to th ose of the known protein phosphatase 1 and 2A inhibitors okadaic acid and calyculin A, which are also tumor promoters. Fostriecin induced vi mentin hyperphosphorylation mostly at two sites, which were sensitive to staurosporine and could be phosphorylated by protein kinase C in vi tro, Fostriecin-induced vimentin hyperphosphorylation also occurred in cells that lack p34(cdc2) kinase activity, These results suggest that protein kinase C plays a direct or indirect role in vimentin hyperpho sphorylation during exposure to fostriecin, The results also provide s trong evidence that fostriecin inhibits protein phosphatases 1 and 2A in vivo and raise the possibility that it may have tumor-promoting act ivity.