Lovastatin alters cytoskeleton organization and inhibits experimental metastasis of mammary carcinoma cells

Abstract

Lovastatin is a competitive inhibitor of 3-hydroxy 3-methylglutaryl coenzyme A reductase, the key regulatory enzyme of cholesterol biosynthesis. This enzyme catalyzes the formation of mevalonate, which is also the precursor of isoprenoid moieties, such as farnesol and geraniol, that are incorporated into several molecules essential for tumor cell signaling. Here, we describe that pretreatment with a non-cytotoxic concentration of lovastatin (10 microM) dramatically inhibited the metastatic ability of F311 mammary carcinoma cells in syngeneic BALB/c mice. Similarly, daily i.p. treatment of animals with a well-tolerated dose of lovastatin (10 mg/kg/day) significantly reduced the number of experimental lung metastases. In vitro, incubation of F3II monolayers in the presence of lovastatin caused a rounded-cell morphology. Immunofluorescence analysis revealed a lack of cortical actin organization, micrutubule disruption and inhibition of integrin-mediated focal contacts in lovastatin-treated cells. Exposure of F3II cells to lovastatin significantly inhibited tumor cell adhesion and migration, and coincubation with the cholesterol precursor mevalonate prevented these effects. Lovastatin reduced membrane localization of Rho protein, a signaling molecule involved in the regulation of actin-based cell motility that needs geranylation for membrane association and activation. In addition, lovastatin induced a dose-dependent inhibition in the secretion of urokinase, a key proteolytic enzyme during tumor invasion and metastasis, and a significant increase of tissue-type plasminogen activator, a marker of good prognosis in mammary cancer. These data suggest that antimetastatic properties of lovastatin are strongly associated with alterations in cytoskeleton organization and the consequent modulation of adhesion, motility and proteolysis.