Activation of Estrogen receptor (ER) a (a) promotes cell growth and influences the response of cancer cell to chemotherapeutic agents. However, the mechanism by which ERa activation antagonizes cells to chemotherapy-induced cytotoxicity remains unclear. Here, we investigated the effect of cisplatin on ERa activation. In addition, we examined whether down-regulation of ERa modulate cisplatin-mediated cytotoxicity using 2 human ovarian cancer cells (Caov-3 and Ovcar-3) transduced with ERa short hairpin RNA (shRNA). The proliferation assay showed that 17b-estradiol (E2) induced cell proliferation via activation of Akt and extracellular signal-regulated kinase (ERK) cascades, while shRNA mediated downregulation of ERa inhibited the cell proliferation. Immunoblot analysis revealed that cisplatin induced the phosphorylation of ERa at serine 118 via ERK cascade. Luciferase assay showed that cisplatin increases transcriptional activity of estrogen-responsive element (ERE). The E2-stimulated ERa activation attenuated cisplatin-induced cytotoxicity. Meanwhile, down-regulation of ERa inhibited E2-induced protective effect on cisplatin toxicity as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Moreover, Pretreatment with E2 followed by cisplatin decreased the expression of cleaved PARP, and increased the expression of anti-apoptotic protein Bcl-2. Collectively, our findings suggest that activation of ERa by E2 and cisplatin can induce platinum-resistance by increasing the expression of antiapoptotic protein in ovarian cancer cells. Therefore, our findings provide valuable information that ERa might be a promising therapeutic target for platinum-resistant ovarian cancer.Abbreviations: ER, estrogen receptor; ERK, extracellular signal regulated protein kinase; PI3K, phosphatidylinositol 3-kinase.

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Oxidative stress in the visceral fat is higher in postmenopausal women. The expression of the antioxidant genes HO-1, NQO1, and GCL was upregulated by estrogen in 3T3-L1 adipocytes. Hence, estrogen may act as an antioxidant in the adipose tissues of premenopausal women.