title: Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer.
abstract: Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and ARv567esas well as full-length AR. Treatment of mice xenografted with ARV-driven CRPC tumors with a drug-like small-molecule Sigma1 inhibitor significantly inhibited tumor growth associated with elimination of AR and ARV7 in responsive tumors. Together, our data show that Sigma1 modulators can be used to suppress AR/ARV-driven prostate cancer cells via regulation of pharmacologically responsive Sigma1-AR/ARV interactions, bothin vitroandin vivoCancer Res; 77(9); 2439-52. ©2017 AACR.
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Thomas
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Longen
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Halley M
authors.initials: HM
authors.lastname: Oyer
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Maher
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Salvino
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Blase
authors.initials: B
authors.lastname: Kania
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Kelsey N
authors.initials: KN
authors.lastname: Anderson
authors.affiliation: Department of Cancer Biology, Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: William F
authors.initials: WF
authors.lastname: Ostrander
authors.affiliation: Department of Cancer Biology, Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania. fkim@drexelmed.edu.|Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Kim
mesh_terms: D015068:17-Ketosteroids / Q000378:metabolism; D000726:Androgen Antagonists / Q000008:administration & dosage; D000728:Androgens / Q000378:metabolism; D000732:Androstanols / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000097605:Sigma-1 Receptor
chemical_list: D015068:17-Ketosteroids; D000726:Androgen Antagonists; D000728:Androgens; D000732:Androstanols; D020033:Protein Isoforms; D011944:Receptors, Androgen; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C418023:5-dihydrorubrosterone; C410798:AR protein, human