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

Cancer Biol Ther. 2017 Sep 2;18(9):730-739. doi: 10.1080/15384047.2016.1235656. Epub 2016 Sep 30.


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

Keywords: Cisplatin; ERK; drug resistance; estrogen receptor; ovarian cancer.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm / drug effects*
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / agonists*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Humans
  • MAP Kinase Signaling System
  • Ovarian Neoplasms / metabolism*
  • Phosphorylation
  • Platinum / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Small Interfering / genetics


  • Antineoplastic Agents
  • BCL2 protein, human
  • Estrogen Receptor alpha
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Platinum
  • Estradiol
  • Cisplatin