INHIBITION OF B16 MELANOMA CELL-PROLIFERATION AND ALTERATIONS IN P21 RAS EXPRESSION INDUCED BY INTERCEPTORS OF SIGNAL-TRANSDUCTION PATHWAYS

Anti-tumor effects of agents known to intervene with signal transducti on pathways (ras and protein kinase c cascades) were examined in the B 16 melanoma cell model. The compounds examined included: lovastatin, a n inhibitor of HMG-CoA reductase, which interfers with membrane locali zation of p21 ras protein; H-7, a classic inhibitor of protein kinase C; and tiazofurin, a GTP depleting agent, that might affect the GTP/GD P ratio on p21ras. The three agents were-found to inhibit the prolifer ation of B16 melanoma cells. Only tiazofurin, as expected, induced a s ignificant decrease in GTP levels. Lovastatin and H-7 altered p21 subc ellular localization. They reduced membrane expression of p21 ras, whi le increasing its expression in the cytosol. Following tiazofurin trea tment a trend towards increased membranal p21 was observed. These resu lts suggest that p21 is a target for the action of signal transduction inhibitors. However, the relationship between growth inhibition and a ltered p21 expression is not yet clear.