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Updated: Mar 7, 2026
08:49
Murine Prostate Micro-dissection and Surgical Castration
Published on: May 11, 2016
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Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer.
Jeffrey D Thomas1, Charles G Longen1, Halley M Oyer1
1Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
Cancer Research
|February 26, 2017
Summary
Small molecule Sigma1 inhibitors can suppress androgen receptor (AR) and AR splice variant (ARV) signaling in prostate cancer. This approach targets AR/ARV-driven castration-resistant prostate cancer (CRPC) by degrading AR proteins and inhibiting tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Androgen receptor (AR) signaling drives prostate cancer, but resistance develops through AR reactivation.
- Castration-resistant prostate cancer (CRPC) often involves AR splice variants (ARVs).
- Sigma1 (sigma-1 receptor) is a chaperone protein involved in protein homeostasis.
Purpose of the Study:
- To investigate if Sigma1 inhibitors can suppress AR and ARV activity in prostate cancer.
- To explore the therapeutic potential of targeting Sigma1-AR interactions in CRPC.
Main Methods:
- Treatment with small-molecule Sigma1 inhibitors.
- RNA interference (RNAi) knockdown of Sigma1.
- Assessment of AR and ARV nuclear translocation, protein degradation, and transcriptional activity.
- Co-immunoprecipitation to study Sigma1-AR/ARV interactions.
- In vivo studies using mouse xenograft models of CRPC.
Main Results:
- Sigma1 inhibition prevented AR nuclear translocation and induced proteasomal degradation of AR and ARVs.
- Knockdown of Sigma1 decreased AR levels and activity.
- Sigma1 was found to physically associate with full-length AR and ARVs (ARV7, ARv567es).
- In vivo, Sigma1 inhibitor treatment significantly inhibited CRPC tumor growth and reduced AR/ARV levels.
Conclusions:
- Sigma1 modulators can suppress AR and ARV signaling in prostate cancer cells.
- Targeting Sigma1-AR/ARV interactions offers a potential therapeutic strategy for CRPC.
- Sigma1 inhibitors demonstrate efficacy both in vitro and in vivo for AR/ARV-driven prostate cancer.
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