Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen-dependent and castration-resistant prostate cancer cells.

Background: Prostate cancer (PCa) is diagnosed at the highest rate of all non-cutaneous male cancers in the United States. The androgen-dependent (AD) transcription factor, androgen receptor (AR), drives PCa-but inhibiting AR or androgen biosynthesis induces remission for only a short time. At which point, patients acquire more aggressive castration-resistant (CR) disease with re-activated AR-dependent signaling. To combat treatment resistance, down-regulating AR protein expression has been considered as a potential treatment strategy for CR-PCa.

Methods: AD- and CR-PCa cell lines were treated with the well-tolerated FDA-approved oral medicine, riluzole. Expression of full-length or wild-type AR (AR-FL) and constitutively active AR-splice variant 7 (AR-V7) was assessed by immunoblotting. AR-FL/AR-V7 activity was measured using qRT-PCR of AR-target genes. Cytoplasmic [Ca ] levels were measured using a fluorescent Ca indicator microplate assay. Markers of the endoplasmic reticulum stress (ERS) pathway and autophagy were assessed by immunoblotting. Direct interaction between AR and selective autophagy receptor p62 was demonstrated by co-immunoprecipitation.

Results: We demonstrate that riluzole downregulates AR-FL, mutant ARs, and AR-V7 proteins expression by protein degradation through ERS pathway and selective autophagy. Riluzole also significantly inhibited AR transcription activity by decreasing its target genes expression (PSA, TMPRSS2, and KLK2).

Conclusions: We provide key mechanistic insights by which riluzole exerts its anti-tumorigenic effects and induces AR protein degradation via ERS pathways. Our findings support the potential utility of riluzole for treatment of PCa.