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

ABSTRACT: Activation of Estrogen receptor (ER) ? (?) promotes cell growth and influences the response of cancer cell to chemotherapeutic agents. However, the mechanism by which ER? activation antagonizes cells to chemotherapy-induced cytotoxicity remains unclear. Here, we investigated the effect of cisplatin on ER? activation. In addition, we examined whether down-regulation of ER? modulate cisplatin-mediated cytotoxicity using 2 human ovarian cancer cells (Caov-3 and Ovcar-3) transduced with ER? short hairpin RNA (shRNA). The proliferation assay showed that 17?-estradiol (E2) induced cell proliferation via activation of Akt and extracellular signal-regulated kinase (ERK) cascades, while shRNA mediated downregulation of ER? inhibited the cell proliferation. Immunoblot analysis revealed that cisplatin induced the phosphorylation of ER? at serine 118 via ERK cascade. Luciferase assay showed that cisplatin increases transcriptional activity of estrogen-responsive element (ERE). The E2-stimulated ER? activation attenuated cisplatin-induced cytotoxicity. Meanwhile, down-regulation of ER? 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? by E2 and cisplatin can induce platinum-resistance by increasing the expression of anti-apoptotic protein in ovarian cancer cells. Therefore, our findings provide valuable information that ER? might be a promising therapeutic target for platinum-resistant ovarian cancer.

SUBMITTER: Matsumura S 

PROVIDER: S-EPMC5663418 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature