Glucocorticoid receptor activation inhibits chemotherapy-induced cell death in high-grade serous ovarian carcinoma

Gynecol Oncol. 2015 Sep;138(3):656-62. doi: 10.1016/j.ygyno.2015.06.033. Epub 2015 Jun 24.


Objectives: To test the hypothesis that glucocorticoid receptor (GR) activation increases resistance to chemotherapy in high-grade serous ovarian cancer (HGS-OvCa) and that treatment with a GR antagonist will improve sensitivity to chemotherapy.

Methods: GR expression was assessed in OvCa cell lines by qRT-PCR and Western blot analysis and in xenografts and primary human tumors using immunohistochemistry (IHC). We also examined the effect of GR activation versus inhibition on chemotherapy-induced cytotoxicity in OvCa cell lines and in a xenograft model.

Results: With the exception of IGROV-1 cells, all OvCa cell lines tested had detectable GR expression by Western blot and qRT-PCR analysis. Twenty-five out of the 27 human primary HGS-OvCas examined expressed GR by IHC. No cell line expressed detectable progesterone receptor (PR) or androgen receptor (AR) by Western blot analysis. In vitro assays showed that in GR-positive HeyA8 and SKOV3 cells, dexamethasone (100nM) treatment upregulated the pro-survival genes SGK1 and MKP1/DUSP1 and inhibited carboplatin/gemcitabine-induced cell death. Concurrent treatment with two GR antagonists, either mifepristone (100nM) or CORT125134 (100nM), partially reversed these effects. There was no anti-apoptotic effect of dexamethasone on chemotherapy-induced cell death in IGROV-1 cells, which did not have detectable GR protein. Mifepristone treatment alone was not cytotoxic in any cell line. HeyA8 OvCa xenograft studies demonstrated that adding mifepristone to carboplatin/gemcitabine increased tumor shrinkage by 48% compared to carboplatin/gemcitabine treatment alone (P=0.0004).

Conclusions: These results suggest that GR antagonism sensitizes GR+ OvCa to chemotherapy-induced cell death through inhibition of GR-mediated cell survival pathways.

Keywords: Chemotherapy; GR antagonist; Mifepristone; Ovarian cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Carcinoma, Ovarian Epithelial
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cystadenocarcinoma, Serous / drug therapy*
  • Cystadenocarcinoma, Serous / metabolism*
  • Cystadenocarcinoma, Serous / pathology
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Immunohistochemistry
  • MCF-7 Cells
  • Mice
  • Mice, SCID
  • Mifepristone / pharmacology
  • Neoplasms, Glandular and Epithelial / drug therapy*
  • Neoplasms, Glandular and Epithelial / metabolism*
  • Neoplasms, Glandular and Epithelial / pathology
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Random Allocation
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Receptors, Glucocorticoid / metabolism*
  • Xenograft Model Antitumor Assays


  • Receptors, Glucocorticoid
  • Mifepristone