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

Erica M. Stringer-Reasor, Gabrielle M. Baker, Maxwell N. Skor, Masha Kocherginsky, Ernst Lengyel, Gini F. Fleming*, Suzanne D. Conzen

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 (100 nM) 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 (100 nM) or CORT125134 (100 nM), 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.

Original languageEnglish (US)
Pages (from-to)656-662
Number of pages7
JournalGynecologic oncology
Volume138
Issue number3
DOIs
StatePublished - Sep 1 2015

Fingerprint

Glucocorticoid Receptors
Cell Death
Carcinoma
Drug Therapy
gemcitabine
Mifepristone
Carboplatin
Cell Line
Heterografts
Western Blotting
Dexamethasone
Immunohistochemistry
Therapeutics
Polymerase Chain Reaction
Androgen Receptors
Progesterone Receptors
Ovarian Neoplasms
Neoplasms
Cell Survival

Keywords

  • Chemotherapy
  • GR antagonist
  • Mifepristone
  • Ovarian cancer

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

Cite this

Stringer-Reasor, Erica M. ; Baker, Gabrielle M. ; Skor, Maxwell N. ; Kocherginsky, Masha ; Lengyel, Ernst ; Fleming, Gini F. ; Conzen, Suzanne D. / Glucocorticoid receptor activation inhibits chemotherapy-induced cell death in high-grade serous ovarian carcinoma. In: Gynecologic oncology. 2015 ; Vol. 138, No. 3. pp. 656-662.
@article{878b09caa22c4c07b76cad6a2e3f9cec,
title = "Glucocorticoid receptor activation inhibits chemotherapy-induced cell death in high-grade serous ovarian carcinoma",
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 (100 nM) 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 (100 nM) or CORT125134 (100 nM), 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",
author = "Stringer-Reasor, {Erica M.} and Baker, {Gabrielle M.} and Skor, {Maxwell N.} and Masha Kocherginsky and Ernst Lengyel and Fleming, {Gini F.} and Conzen, {Suzanne D.}",
year = "2015",
month = "9",
day = "1",
doi = "10.1016/j.ygyno.2015.06.033",
language = "English (US)",
volume = "138",
pages = "656--662",
journal = "Gynecologic Oncology",
issn = "0090-8258",
publisher = "Academic Press Inc.",
number = "3",

}

Glucocorticoid receptor activation inhibits chemotherapy-induced cell death in high-grade serous ovarian carcinoma. / Stringer-Reasor, Erica M.; Baker, Gabrielle M.; Skor, Maxwell N.; Kocherginsky, Masha; Lengyel, Ernst; Fleming, Gini F.; Conzen, Suzanne D.

In: Gynecologic oncology, Vol. 138, No. 3, 01.09.2015, p. 656-662.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Glucocorticoid receptor activation inhibits chemotherapy-induced cell death in high-grade serous ovarian carcinoma

AU - Stringer-Reasor, Erica M.

AU - Baker, Gabrielle M.

AU - Skor, Maxwell N.

AU - Kocherginsky, Masha

AU - Lengyel, Ernst

AU - Fleming, Gini F.

AU - Conzen, Suzanne D.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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 (100 nM) 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 (100 nM) or CORT125134 (100 nM), 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.

AB - 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 (100 nM) 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 (100 nM) or CORT125134 (100 nM), 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.

KW - Chemotherapy

KW - GR antagonist

KW - Mifepristone

KW - Ovarian cancer

UR - http://www.scopus.com/inward/record.url?scp=84941422784&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941422784&partnerID=8YFLogxK

U2 - 10.1016/j.ygyno.2015.06.033

DO - 10.1016/j.ygyno.2015.06.033

M3 - Article

VL - 138

SP - 656

EP - 662

JO - Gynecologic Oncology

JF - Gynecologic Oncology

SN - 0090-8258

IS - 3

ER -