INHIBITION OF RAS P21 MEMBRANE LOCALIZATION AND MODULATION OF PROTEIN-KINASE-C ISOZYME EXPRESSION DURING REGRESSION OF CHEMICAL CARCINOGEN-INDUCED MURINE SKIN TUMORS BY LOVASTATIN

We investigated the ras p21 membrane localization and the expression a nd activation of protein kinase C (PKC) isozymes in activated ras onco gene-containing tumors and assessed whether these events were related to tumor growth. We used 7,12-dimethylbenz[a]anthracene-initiated and 12-O-tetradecanoylphorbol-13-acetate-promoted SENCAR mouse skin tumors , which were shown to contain Ha-ras oncogene activated by point mutat ion at codon 61, as an in vivo model for these studies. Compared with levels in epidermis, highly elevated levels of membrane-bound Ha-ras p 21 were observed in growing tumors, which also showed strong expressio n and membrane translocation of PKC zeta and beta II and weak expressi on of PCK alpha. However, when ras p21 membrane localization was block ed in vivo in growing tumors by lovastatin, opposite results were evid ent. Compared with saline-treated animals, in which tumor growth conti nued, lovastatin-treated animals had significantly inhibited tumor gro wth, which led to tumor regression with concomitant inhibition of Ha-r as pZ1 membrane localization. These regressing tumors from lovastatin- treated animials also showed a decrease in the expression and membrane translocation of PKC zeta and beta II but increased expression of PKC alpha. Taken together, our results indicate that ras pZ1 membrane loc alization and the expression and activation of PKC zeta, beta II, and alpha may be the critical events in the regulation of the growth of tu mors that contain activated I-as oncogenes. (C) 1995 Wiley-Liss, Inc.