MnSOD和铁转运在他汀介导的乳腺癌细胞死亡中的作用

　　ROLE OF MnSOD AND IRON TRANSPORT IN STATIN-MEDIATED BREAST CANCER CELL DEATH

　　A.K. Kanugula, S. Kotamraju

　　Centre for Chemical Biology, Indian Institute of Chemical Technology, Hyderabad, India

　　HMG-CoA reductase inhibitors (statins) are FDA-approved drugs that are widely used to lower cholesterol levels in hyperlipedemic patients. Statins exert other pleotropic beneficial effects which are independent of their cholesterol lowering properties. Emerging data indicates that statins can induce cell death of variety of cancers including breast cancer cells. Earlier we have shown that statin-induced breast cancer death involves nitric oxide and arginine-dependent pathways in MCF-7 cells (Kotamraju S. et al. Cancer Res. 2007). We show that only lipophilic statins (fluvastatin and simvastatin) but not hydrophilic statins (pravastatin) induced MCF-7 and MDA-MB-231 cell death. The objective of the current study was to see whether mitochondrial component is involved in statin mediated breast cancer cell death. It was observed that both fluvastatin and simvastain dose and time-dependently increased the expression and activity of MnSOD, a major mitochondrial superoxide scavenging enzyme. This effect was correlated with a decrease in the expression of DDB2, a transcriptional negative regulator of MnSOD. Transcriptional repression of DDB2 and stimulation of MnSOD activity leading to the proapoptotic effects of statins occurred through inhibition of geranylgeranylation pathways. The antiproliferative effects of statins were coincided with a decreased expression of transferrin receptor (TfR), a major iron transport protein in cancer cells. We conclude that increased MnSOD activity and a reduction in the iron transport are in part responsible for the antiproliferative and tumoricidal effects of statin drugs

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