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 AR
Thomas, Jeffrey D.; Longen, Charles G.; Oyer, Halley M.; Chen, Nan; Maher, Christina M.; Salvino, Joseph M.; Kania, Blase; Anderson, Kelsey N.; Ostrander, William F.; Knudsen, Karen E.; and Kim, Felix J., "Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer." (2017). Department of Cancer Biology Faculty Papers. Paper 133.