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

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 ®ber 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 e ects. That is, RhoA was activated, actin stress ®bers were assembled, the cells assumed a¯at 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 ®bers 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 e ects 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.

RhoA Prenylation Is Required for Promotion of Cell Growth and Transformation and Cytoskeleton Organization but Not for Induction of Serum Response Element Transcription

“…4A). Similar changes of cell size were observed in Swiss 3T3 cells microinjected with active RhoA (3) as well as in murine tumor cells (50).…”

Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21CIP1 levels in androgen-independent human prostate cancer cells

“…Moreover, these Rho GTPases each appear to be necessary and sufficient for progression through the G1 phase of the cell cycle in fibroblasts (Olsen et al, 1995). RhoA has been shown to specifically participate in signaling pathways controlling prostate epithelial cell proliferation using a cell line derived from transgenic mice exhibiting prostate adenocarcinoma (TRAMP model) (Ghosh et al, 1999;Ghosh et al, 2002).…”

The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells

“…9,10 Lovastatin inhibits the proliferation of several tumor cells by inducing a growth arrest at the G1/S boundary. 10,11 Furthermore, lovastatin has a chemosensitizing capacity in cancer cells, rendering tumor cells susceptible to chemotherapeutic drugs [12][13][14][15][16][17][18] and can directly induce apoptosis as has been documented for several tumor cell lines 10,15,19,20 and tumor cells from patients with acute myeloid leukemia, 19 possibly via down-regulation of the anti-apoptotic protein Bcl-2. 15 The observation that long-term treatment of hypercholesterolemia patients with statins was associated with fewer cancer deaths 21 suggests that lovastatin interferes with processes involved in tumorigenesis.…”