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 and activation of protein kinase C (PKC) isozymes in activated ras oncogene-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 mutation at codon 61, as an in vivo model for these studies. Compared with levels in epidermis, highly elevated levels of membrane-bound Ha-ras p21 were observed in growing tumors, which also showed strong expression and membrane translocation of PKC zeta and beta II and weak expression of PCK alpha. However, when ras p21 membrane localization was blocked in vivo in growing tumors by lovastatin, opposite results were evident. Compared with saline-treated animals, in which tumor growth continued, lovastatin-treated animals had significantly inhibited tumor growth, which led to tumor regression with concomitant inhibition of Ha-ras p21 membrane localization. These regressing tumors from lovastatin-treated animals 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 p21 membrane localization and the expression and activation of PKC zeta, beta II, and alpha may be the critical events in the regulation of the growth of tumors that contain activated ras oncogenes.
Khan
S G
SG
Department of Dermatology, University Hospitals of Cleveland, Ohio 44106, USA.
Saxena
R
R
Bickers
D R
DR
Mukhtar
H
H
Agarwal
R
R
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D007527:Isoenzymes / Q000096:biosynthesis*; D008148:Lovastatin / Q000627:therapeutic use*; D051379:Mice; D018632:Mice, Inbred SENCAR; D010212:Papilloma / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000096:biosynthesis*; D011499:Protein Processing, Post-Translational; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
D007527:Isoenzymes; D015127:9,10-Dimethyl-1,2-benzanthracene; D008148:Lovastatin; D011493:Protein Kinase C; D016283:Proto-Oncogene Proteins p21(ras)