title: Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer.
abstract: Despite new treatments for castrate-resistant prostate cancer (CRPC), the prognosis of patients with CRPC remains bleak due to acquired resistance to androgen receptor (AR)-directed therapy. The glucocorticoid receptor (GR) and AR share several transcriptional targets, including the anti-apoptotic genes serum and glucocorticoid-regulated kinase 1 (SGK1) and Map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Because GR expression increases in a subset of primary prostate cancer (PC) following androgen deprivation therapy, we sought to determine whether GR activation can contribute to resistance to AR-directed therapy. We studied CWR-22Rv1 and LAPC4 AR/GR-expressing PC cell lines following treatment with combinations of the androgen R1881, AR antagonist MDV3100, GR agonist dexamethasone, GR antagonists mifepristone and CORT 122928, or the SGK1 inhibitor GSK650394. Cell lines stably expressing GR (NR3C1)-targeted shRNA or ectopic SGK1-Flag were also studied in vivo. GR activation diminished the effects of the AR antagonist MDV3100 on tumor cell viability. In addition, GR activation increased prostate-specific antigen (PSA) secretion and induced SGKI and MKP1/DUSP gene expression. Glucocorticoid-mediated cell viability was diminished by a GR antagonist or by co-treatment with the SGK1 inhibitor GSK650394. In vivo, GR depletion delayed castrate-resistant tumor formation, while SGK1-Flag-overexpressing PC xenografts displayed accelerated castrate-resistant tumor initiation, supporting a role for SGK1 in GR-mediated CRPC progression. We studied several PC models before and following treatment with androgen blockade and found that increased GR expression and activity contributed to tumor-promoting PC cell viability. Increased GR-regulated SGK1 expression appears, at least in part, to mediate enhanced PC cell survival. Therefore, GR and/or SGK1 inhibition may be useful adjuncts to AR blockade for treating CRPC.
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, The University of Chicago, 5841 S. Maryland Ave. MC 2115, Chicago, IL, 60637, USA.
authors.forename: Masis
authors.initials: M
authors.lastname: Isikbay
authors.forename: Kristen
authors.initials: K
authors.lastname: Otto
authors.forename: Steven
authors.initials: S
authors.lastname: Kregel
authors.forename: Jacob
authors.initials: J
authors.lastname: Kach
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Vander Griend
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Conzen
authors.forename: Russell Z
authors.initials: RZ
authors.lastname: Szmulewitz
mesh_terms: D059002:Androgen Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D001565:Benzoates / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D008297:Male; D015741:Metribolone / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D059002:Androgen Receptor Antagonists; D001549:Benzamides; D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003907:Dexamethasone; D017874:Immediate-Early Proteins; D015741:Metribolone; D015735:Mifepristone; D009570:Nitriles; D010669:Phenylthiohydantoin; D017346:Protein Serine-Threonine Kinases; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D000099184:Serum-Glucocorticoid Regulated Kinases; C497713:NR3C1 protein, human; C532254:2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid; C540278:enzalutamide