Abstract 5281: Role of TMEM97/Sigma-2 receptor in prostate cancer

Abstract

Abstract Introduction: Prostate cancer is the most common cancer in men. About one in eight men will be diagnosed with prostate cancer in his lifetime, and one in forty-one men will die of it. Sigma 2 receptor (σ2R) has been implicated in carcinogenesis including prostate cancer. Its molecular identity remained elusive until 2017 that transmembrane protein 97 (TMEM97) was identified as the bona fide sigma 2 receptor. Past studies have shown that σ2R is highly expressed in various mammalian tumors and TMEM97 works as an oncogene in different cancers. In this study, we examined the expression of TMEM97/σ2 receptor in prostate cancer, evaluated its interaction with androgen receptor (AR), and determined its functions in tumor cell growth and progression. Methods: The expression of TMEM97 at mRNA levels and its association with clinical parameters were queried in the TCGA database using cBioportal. Its expression pattern in prostate tumor tissues was examined by IHC using a commercially validated antibody. A correlation analysis of TMEM97 with AR was conducted utilizing both PCTA and TCGA databases. To determine its roles in tumor proliferation, clonogenicity, and responses to hormone deprivation and chemo-therapy, TMEM97 expression was overexpressed and knocked down, and the subsequent effects were determined by cell proliferation MTS assay, colony formation assay with and without enzalutamide treatment. A xenograft model of nu/nu mice was used to assess the impact of TMEM97 overexpression on tumor formation and growth in vivo. The effects of TMEM97 overexpression and knockdown on AR transcriptional activity were examined. Results: A significant elevation of TMEM97 mRNA levels, with a Z-Score above 2.0, was found in 5% of the prostate cancer patients and was associated with significantly reduced survival. TMEM97 protein was detected in prostate tumor tissues of all stages and grades. Its expression is highly correlated with the expression of AR in prostate cancer. Prostate cancer cells with TMEM97 overexpression showed growth advantage over the control cells both in normal culture conditions and also under treatment of enzalutamide. TMEM97 knockdown weakened growth, and sensitized castration resistant 22Rv1 toward enzalutamide, which is linked to the decrease of AR-V7. TMEM97 overexpression in LNCaP cells also significantly increased tumor formation and growth when xenografted into nu/nu mice. In LNCaP cells, TMEM97 overexpression elevated AR target genes expression. Parallelly, these genes were all significantly downregulated in TMEM97 knockdown cells. A compound with a high affinity to TMEM97 was found to induce apoptosis of prostate cancer cells with preferential degradation of AR-V7. Conclusion: The observations suggest that TMEM97/sigma2 receptor plays a role in prostate tumor cell proliferation and the increased expression of TMEM97 can elevate AR activity and stimulate prostate tumor formation and growth. Citation Format: Xiangwei Fang, Yuanqin Zhang, Jiuhui Wang, Paul Cacioppo, Michael Crider, Daotai Nie. Role of TMEM97/Sigma-2 receptor in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5281.