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
✍ Scribed by Sikandar G. Khan; Ramesh Saxena; David R. Bickers; Hasan Mukhtar; Rajesh Agarwal
- Publisher
- John Wiley and Sons
- Year
- 1995
- Tongue
- English
- Weight
- 832 KB
- Volume
- 12
- Category
- Article
- ISSN
- 0899-1987
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✦ Synopsis
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 t o tumor growth. We used 7,12-dirnethylbenz[a]anthracene-initiated and 12-O-tetradecanoylphorbol-13acetate-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 6 and pll and weak expression o f PCK a. 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 t o tumor regression with concomitant inhibition of Ha-ras p21 membrane localization. These regressing tumors from lovastatin-treated animials also showed a decrease in the expression and membrane translocation of PKC < and pll but increased expression of PKC a. Taken together, our results indicate that ras p21 membrane localization and the expression and activation o f PKC 6, pll, and a may be the critical events in the regulation o f the growth of tumors that contain activated ras Oncogenes.