Simvastatin and lovastatin inhibit breast cell invasion induced by H-Ras.
Breast cancer mortality is strongly related to the invasive and metastatic potential of tumor cells. We previously showed that an active mutant of H-Ras induced invasive phenotype of MCF10A human breast epithelial cells. Membrane anchoring of Ras requires isoprenylation which involves the activity of 3-hydroxy 3-methylglutaryl (HMG)-CoA reductase. In this study, we investigated the inhibitory effect of HMG-CoA reductase inhibitors, widely used for hypercholesterolemia, on H-Ras-induced invasion of MCF10A cells. Treatment of H-Ras MCF10A cells with simvastatin and lovastatin markedly decreased isoprenylated H-Ras in membrane fraction while the unprenylated H-Ras was increased in cytosol fraction, demonstrating that these statins inhibited membrane anchoring of H-Ras in MCF10A cells. Simvastatin and lovastatin significantly inhibited H-Ras-induced invasion which was reversed by farnesyl pyrophosphate (FPP), indicating that the inhibitory effect was related to inhibition of the biosynthesis of prenylated derivatives. Statins downregulated matrix metalloproteinase (MMP)-9 and, to a lesser extent, MMP-2 in H-Ras MCF10A cells. Simvastatin and lovastatin inactivated H-Ras downstream signaling molecules, possibly by inhibiting H-Ras membrane localization and thus its function in MCF10A cells. Taken together, this study clearly demonstrated the inhibitory effect of simvastatin and lovastatin on H-Ras-induced invasion, MMP expression and signal transduction in MCF10A breast epithelial cells, providing supporting rationale for future statin trials as a therapeutic intervention to regulate breast cancer metastasis.
Kang
Soouk
S
College of Pharmacy, Duksung Women's University, Seoul 132-714, Korea.
Kim
Eun-Sook
ES
Moon
Aree
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology*; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; D008148:Lovastatin; D019821:Simvastatin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D018631:ras Proteins