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

S. G. Khan, R. Saxena, D. R. Bickers, H. Mukhtar, R. Agarwal

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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 tumors 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 ζ and βII and weak expression of PCK α. 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 ζ and βII but increased expression of PKC α. Taken together, our results indicate that ras p21 membrane localization and the expression and activation of PKC ζ, βII, and α may be the critical events in the regulation of the growth of tumors that contain activated ras oncogenes. © 1995 Wiley‐Liss Inc.

Original languageEnglish (US)
Pages (from-to)205-212
Number of pages8
JournalMolecular Carcinogenesis
Volume12
Issue number4
DOIs
StatePublished - Apr 1995

Keywords

  • farnesyltransferase
  • isoprenylation
  • ras oncogene
  • signal transduction
  • tumorigenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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