Metastatic
melanoma is a life-threatening disease for which no effective treatment is currently available. In
melanoma cells, Rho overexpression promotes invasion and
metastasis. However, the effect of
statins on spontaneous
metastasis and
tumor growth remains unclear. In the present study, we investigated the mechanism of
statin-mediated
tumor growth and
metastasis inhibition in an in vivo model. We found that
statins significantly inhibited spontaneous
metastasis and
tumor growth.
Statins inhibited the
mRNA expression and enzymatic activities of
matrix metalloproteinases (
MMPs) in vivo and also suppressed the
mRNA and
protein expression of very late
antigens (VLAs). Moreover,
statins inhibited the prenylation of Rho as well as the phosphorylation of
LIM kinase,
serum response factor (SRF), and c-Fos downstream of the Rho signaling pathway. In addition,
statins enhanced p53, p21, and p27 expression and reduced phosphorylation of
cyclin-dependent kinase and expression of
cyclin D1 and E2. These results indicate that
statins suppress Rho signaling pathways, thereby inhibiting
tumor metastasis and growth. Furthermore,
statins markedly improved the survival rate in a
metastasis model, suggesting that
statins have potential clinical applications for the treatment of metastatic
cancers.