Abstract 250: TMEM97/sigma 2 receptor increases androgen receptor activities to regulate prostate cancer cell growth and sensitivity to castration therapy

Abstract Prostate cancer is one of the most common cancers in men. Suppression of androgen receptor (AR) activity by androgen depletion or direct AR antagonist treatment, although initially effective, leads to emergence of castration-resistant prostate cancer. Sigma 2 receptor (σ2R) has been implicated in carcinogenesis including prostate cancers. Its molecular identity remained elusive until 2017 that transmembrane protein 97 (TMEM97) was identified as the bona fide sigma 2 receptor. Here we report that TMEM97/σ2R expression was elevated in prostate tumors of higher malignancy and advanced stages, and was associated with reduced survival of prostate cancer patients. Via in-vitro studies, increased expression of TMEM97 enhanced prostate cancer cell proliferation, clonogenicity, and resistance to enzalutamide. Knockdown of σ2R expression reduced prostate cancer cell growth and clonogenicity, and sensitized LNCaP and castration resistant 22Rv1 cells towards enzalutamide. There was a positive correlation between TMEM97 and AR expressions in prostate tumors. Knockdown of σ2R expression reduced the protein levels of AR and its AR-V7 variant under hormone deprivation condition. Decreased TMEM97 expression also downregulated AR activities as evidenced by reduced expression of AR target genes. PB-28, a known σ2R agonist, can stimulate AR target genes expressions while antagonist decreased them. SM21, a σ2R antagonist, presented synergism when combined with enzalutamide in the treatment of prostate cancer cells. Our findings suggest a potential approach targeting TMEM97/σ2R to reduce castration resistance. Citation Format: Daotai Nie, Xiangwei Fang, Yuanqin Zhang, Jiuhui Wang. TMEM97/sigma 2 receptor increases androgen receptor activities to regulate prostate cancer cell growth and sensitivity to castration therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 250.