Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line

Paramita M Ghosh, Nandini Ghosh-Choudhury, Marissa L. Moyer, Glen E. Mott, Charles A. Thomas, Barbara A. Foster, Norman M. Greenberg, Jeffrey I. Kreisberg

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Prostate cancer cells derived from transgenic mice with adenocarcinoma of the prostate (TRAMP cells) were treated with the HMG-CoA reductase inhibitor, lovastatin. This caused inactivation of the small GTPase RhoA, actin stress fiber disassembly, cell rounding, growth arrest in the G1 phase of the cell cycle, cell detachment and apoptosis. Addition of geranylgeraniol (GGOL) in the presence of lovastatin, to stimulate protein geranylgeranylation, prevented lovastatin's effects. That is, RhoA was activated, actin stress fibers were assembled, the cells assumed a flat morphology and cell growth resumed. The following observations support an essential role for RhoA in TRAMP cell growth: (1) TRAMP cells expressing dominant-negative RhoA (T19N) mutant protein displayed few actin stress fibers and grew at a slower rate than controls (35 h doubling time for cells expressing RhoA (T19N) vs 20 h for untransfected cells); (2) TRAMP cells expressing constitutively active RhoA (Q63L) mutant protein displayed a contractile phenotype and grew faster than controls (13 h doubling time). Interestingly, addition of farnesol (FOL) with lovastatin, to stimulate protein farnesylation, prevented lovastatin-induced cell rounding, cell detachment and apoptosis, and stimulated cell spreading to a spindle shaped morphology. However, RhoA remained inactive and growth arrest persisted. The morphological effects of FOL addition were prevented in TRAMP cells expressing dominant-negative H-Ras (T17N) mutant protein. Thus, it appears that H-Ras is capable of inducing cell spreading, but incapable of supporting cell proliferation, in the absence of geranyl-geranylated proteins like RhoA.

Original languageEnglish (US)
Pages (from-to)4120-4130
Number of pages11
JournalOncogene
Volume18
Issue number28
DOIs
StatePublished - Jul 15 1999
Externally publishedYes

Keywords

  • Actin stress fibers
  • Farnesol
  • Geranylgeraniol
  • H-Ras
  • Lovastatin
  • RhoA

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Ghosh, P. M., Ghosh-Choudhury, N., Moyer, M. L., Mott, G. E., Thomas, C. A., Foster, B. A., Greenberg, N. M., & Kreisberg, J. I. (1999). Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line. Oncogene, 18(28), 4120-4130. https://doi.org/10.1038/sj.onc.1202792