Activation of estrogen receptor alpha by estradiol and cisplatin induces platinum-resistance in ovarian cancer cells

摘要

Activation of Estrogen receptor (ER) alpha (alpha) promotes cell growth and influences the response of cancer cell to chemotherapeutic agents. However, the mechanism by which ER alpha activation antagonizes cells to chemotherapy-induced cytotoxicity remains unclear. Here, we investigated the effect of cisplatin on ER alpha activation. In addition, we examined whether down-regulation of ER alpha modulate cisplatin-mediated cytotoxicity using 2 human ovarian cancer cells (Caov-3 and Ovcar-3) transduced with ER alpha 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 down-regulation of ER alpha inhibited the cell proliferation. Immunoblot analysis revealed that cisplatin induced the phosphorylation of ER alpha at serine 118 via ERK cascade. Luciferase assay showed that cisplatin increases transcriptional activity of estrogen-responsive element (ERE). The E2-stimulated ER alpha activation attenuated cisplatin-induced cytotoxicity. Meanwhile, down-regulation of ER alpha 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 ER alpha 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 ER alpha might be a promising therapeutic target for platinum-resistant ovarian cancer.