title: Glucocorticoid receptor activation inhibits chemotherapy-induced cell death in high-grade serous ovarian carcinoma.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL, United States.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Stringer-Reasor
authors.affiliation: Pathology, The University of Chicago, Chicago, IL, United States.
authors.forename: Gabrielle M
authors.initials: GM
authors.lastname: Baker
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL, United States.
authors.forename: Maxwell N
authors.initials: MN
authors.lastname: Skor
authors.affiliation: Health Studies, The University of Chicago, Chicago, IL, United States.
authors.forename: Masha
authors.initials: M
authors.lastname: Kocherginsky
authors.affiliation: Obstetrics and Gynecology, The University of Chicago, Chicago, IL, United States.
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL, United States. Electronic address: gfleming@medicine.bsd.uchicago.edu.
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.affiliation: 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.
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Conzen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D015735:Mifepristone / Q000494:pharmacology; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011965:Receptors, Glucocorticoid; D015735:Mifepristone
keywords: Chemotherapy; GR antagonist; Mifepristone; Ovarian cancer