Lovastatin induces Cytoskeleton-Dependent Morphological Changes and Alters the Main Steps of Tumor Invasion in Metastatic Mammary Carcinoma Cells.

FARINA, HERNÁN; BUBLIK, DEBORA; GOMEZ, DANIEL; ALONSO, DANIEL.

EE.UU

Congreso; American Association for Cancer Research (AACR); 2001

American Association for Cancer Research

Lovastatin is a competitive inhibitor of 3-hydroxy 3-methylglutaryl coenzyme A reductase, the key regulatory enzyme of de novo cholesterol biosynthesis. This enzyme catalyzes the formation of mevalonate, which is also the precursor of isoprenoid moieties that are incorporated into several molecules essential for tumor cell signaling. Previously, we have reported that prolonged administration of low doses of lovastatin reduced metastatic dissemination to lungs in mice bearing the highly aggressive F3II mammary carcinoma. In the present work, we evaluated the in vitro effects of non-cytotoxic concentrations of lovastatin (5-10 mM) on cytoskeleton organization, tumor cell adhesion and migration, and tumor-derived proteolytic activity, using the F3II cell line. Incubation of F3II monolayers in the presence of lovastatin for 24 h induced a round morphology in tumor cells. Immunofluorescence analysis revealed lack of cortical actin organization and micrutubule disruption in lovastatin-treated cells. Pretreatment with lovastatin significantly inhibited F3II cell adhesion to the substrate in the presence of serum (p<0.001). Lovastatin also decreased tumor cell migration in the ‘wound assay’ (p<0.001), and coincubation with the cholesterol precursor mevalonate (50-200 mM) prevented this effect on F3II cells. Secretion of metalloproteinases by tumor cells (MMP-9 and MMP-2) was not affected by lovastatin treatment. On the contrary, radial caseinolysis and zymographic analysis of plasminogen activators contained in F3II conditioned media showed that lovastatin induced a dose-dependent inhibition of urokinase and a significant increase in tPA (p<0.001). These data suggest that antitumor properties of non-cytotoxic doses of lovastatin are associated to changes in cytoskeleton organization and alterations in adhesion, proteolysis and motility, the three sequential cellular processes of tumor invasion and metastasis. Fuente: Proceedings of the American Association for Cancer Research