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

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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 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 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.

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

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Proto-Oncogene Proteins p21(ras)
Lovastatin
Carcinogens
Protein Kinases
Isoenzymes
Skin
Membranes
Protein Kinase C
Neoplasms
ras Genes
Growth
Membrane Proteins
Inbred SENCAR Mouse
Tetradecanoylphorbol Acetate
Point Mutation
Epidermis
Codon

Keywords

  • Farnesyltransferase
  • Isoprenylation
  • Ras oncogene
  • Signal transduction
  • Tumorigenesis

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

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

In: Molecular Carcinogenesis, Vol. 12, No. 4, 1995, p. 205-212.

Research output: Contribution to journalArticle

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AU - Mukhtar, H.

AU - Agarwal, R.

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