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

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

Author information

1
Department of Medicine, The University of Chicago, Chicago, IL, United States.
2
Pathology, The University of Chicago, Chicago, IL, United States.
3
Health Studies, The University of Chicago, Chicago, IL, United States.
4
Obstetrics and Gynecology, The University of Chicago, Chicago, IL, United States.
5
Department of Medicine, The University of Chicago, Chicago, IL, United States. Electronic address: gfleming@medicine.bsd.uchicago.edu.
6
Department of Medicine, The University of Chicago, Chicago, IL, United States; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, United States. Electronic address: sconzen@medicine.bsd.uchicago.edu.

Abstract

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

PMID:
26115975
PMCID:
PMC4556542
DOI:
10.1016/j.ygyno.2015.06.033
[Indexed for MEDLINE]
Free PMC Article
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