Journal article
Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer
Cancer research (Chicago, Ill.), v 77(9), pp 2439-2452
01 May 2017
PMID: 28235766
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 5 alpha-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 ARv567es as 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, both in vitro and in vivo.
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Details
- Title
- Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer
- Creators
- Jeffrey D. Thomas - Drexel Univ, Coll Med, Dept Pharmacol & Physiol, 245 N 15th St, Philadelphia, PA 19102 USACharles G. Longen - Drexel Univ, Coll Med, Dept Pharmacol & Physiol, 245 N 15th St, Philadelphia, PA 19102 USAHalley M. Oyer - Drexel UniversityNan Chen - Drexel UniversityChristina M. Maher - Drexel UniversityJoseph M. Salvino - Drexel UniversityBlase Kania - Drexel UniversityKelsey N. Anderson - Drexel UniversityWilliam F. Ostrander - Thomas Jefferson Univ, Sidney Kimmel Coll Med, Dept Canc Biol, Philadelphia, PA 19107 USAKaren E. Knudsen - Thomas Jefferson UniversityFelix J. Kim - Drexel University
- Publication Details
- Cancer research (Chicago, Ill.), v 77(9), pp 2439-2452
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 14
- Grant note
- Sidney Kimmel Cancer Center Pilot Study Award Drexel University Clinical and Translational Research Institute CA099996; CA159945; CA176401; P30CA056036-14 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Coulter-Drexel Translational Research Partnership Program Award R01CA099996 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) American Cancer Society
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000400270100025
- Scopus ID
- 2-s2.0-85019034052
- Other Identifier
- 991021904613804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology