Effects Of HMG-CoA Reductase Inhibitor On Proliferation And Differentiation Of MCF-7 Human Breast Cancer Cells & Its Molecular Mechanisms

Lovastatin, as one sort of statin drugs, can inhibit the activity of the 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, the rate-limiting enzyme of endogenous cholesterol biosynthesis. It has been widely used for the clinical treatment of hypercholesterolaemia. Recently, lovastatin has received much attention because of its wide-range effects on human cancer cells ,such as inhibiting proliferation, inducing apoptosis and reducing metastasis; moreover, it has little side effect on normal cells. However, the detail mechanisms for anti-cancer effects are not yet understood. In this report, we examined the effects of lovastatin at the dosages of 4~16μmol/L on the proliferation and differentiation of MCF-7 human breast cancer cells with MTT test and FCM assay, observed morphological changes with electron microscopy and the gap junctional intercellular communication (GJIC) using the Scrape-Loading and Dye Transfer (SLDT) technique. Meanwhile, we also studied the changes of intracellular calcium concentration with laser scanning confocal microscopy in MCF-7 cells treated with lovastatin for 1~3d, as well as the expression of plasma membrane calcium ATPase isoform 1 (PMCA1) mRNA by RT-PCR. The main results were summarized as follows: 1. After treated with lovastatin for 1~3d, the morphology of MCF-7 cells were significantly changed under light microscope,cell death could be observed in the highest dosage group; Meanwhile, the ultrastructures of MCF-7 cells were changed obviously under electron microscope.2. Lovastatin, at the dosages of 4~16μmol/L, inhibited MCF-7 human breastcancer cells proliferation and arrest MCF-7 cells in the G0/G1 phase of cell cycle, meanwhile it induced differentiation of MCF-7 cells. However, apoptosis in MCF-7 cells treated with lovastatin was not obvious.3. Using laser scanning confocal microscope, we found that lovastatin increased intracellular calcium concentration in MCF-7 cells in a dose-and time -dependent manner, but didn't change the expressions of PMCA1 mRNA in MCF-7 cells.4. Using the Scrape-Loading and Dye Transfer (SLDT) technique, we observed that GJIC could be up-regulated in MCF-7 cells treated with lovastatin for 1~3d. This effect of lovastatin was in a dose-and time-dependent manner. These observations suggest that HMG-CoA reductase inhibitor, lovastatin, has the capabilities of inducing cellular morphological changes, inhibiting proliferation, and arresting MCF-7 cells in G0/G1 phase. Meanwhile, it induces the differentiation of MCF-7 cells. All these effects of lovastatin are in a dose-and time-dependent manner, and maybe correlate with lovastatin increasing intracellular calcium concentration of MCF-7 cells and promoting GJIC function between MCF-7 cells...