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

Oncogene volume 18, pages 4120–4130 (1999)Cite this article

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 geranylgeranylated proteins like RhoA.

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Acknowledgements

We would like to thank Ms Sue Aguilar for her assistance in preparing the manuscript for publication. This work was supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs, and a grant from the San Antonio Cancer Institute.

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Authors and Affiliations

  1. Department of Pathology, University of Texas Health Science Center, San Antonio, Texas, USA

    Paramita M Ghosh, Nandini Ghosh-Choudhury, Marissa L Moyer, Glen E Mott & Jeffrey I Kreisberg

  2. Department of Microbiology, University of Texas Health Science Center, San Antonio, Texas, USA

    Charles A Thomas

  3. Department of Cell Biology, Baylor College of Medicine, Houston, Texas, USA

    Barbara A Foster & Norman M Greenberg

  4. Research and Development Service, Audie Murphy Veterans Hospital, San Antonio, Texas, USA

    Jeffrey I Kreisberg

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Ghosh, P., Ghosh-Choudhury, N., Moyer, M. et al. Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line. Oncogene 18, 4120–4130 (1999). https://doi.org/10.1038/sj.onc.1202792

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