ROLE OF TMEM97/∑2 RECEPTOR IN REGULATING ANDROGEN RECEPTOR ACTIVITIES IN PROSTATE CANCER

Author

Xiangwei Fang, Southern Illinois University CarbondaleFollow

Date of Award

8-1-2024

Degree Name

Doctor of Philosophy

Department

Molecular Biology, Microbiology and Biochemistry

First Advisor

Nie, Daotai

Abstract

Prostate cancer is the most common cancers in men. Androgen receptor (AR) is the primary driver of prostate cancer progression, and androgens are the male hormones to activate AR to simulate prostate cancer cells to grow. Thus, current therapy focuses on stopping androgen biosynthesis or blocking AR. However, suppression of AR activity by androgen depletion or direct AR antagonist treatment leads to emergence of castrate-resistant prostate cancer. Sigma-2 receptor (σ2R) plays an important role in cholesterol homeostasis and has been implicated in carcinogenesis including prostate cancer. Its molecular identity remained elusive until 2017 when 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 tumor cell lines and TMEM97 was proposed as an oncogene in various cancers. We hypothesized that TMEM97/σ2 receptor regulates the expression and activities of androgen receptor and its variants to promote prostate cancer proliferation, and it can be a novel target of intervention to reduce AR oncogenic signaling in prostate cancer. The goal of this study is to define the role of TMEM97/σ2 receptor in prostate cancer, to unveil the mechanisms of TMEM97-AR interactions, and to explore therapeutic opportunity targeting TMEM97/σ2 receptor.Here we demonstrated that elevated TMEM97/σ2 receptor was found in prostate tumors of higher malignancy and advanced stages, and was associated with reduced survival of prostate cancer patients. Increased expression of TMEM97 enhanced prostate cancer cell proliferation, clonogenicity, and enzalutamide resistance. Knockdown of σ2 receptor 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 cancers. Sigma-2 receptor knockdown reduced the protein expression of AR and its AR-V7 variant under hormone deprivation condition. Decreased TMEM97 also downregulated AR activities by inhibiting expression of prostate cancer maker genes and AR target genes. Its physical interaction with sigma-1 receptor was noticed, which may contribute to the regulation of AR. Sigma-2 receptor agonist can stimulate AR target genes expressions while antagonist decreased them. In addition, sigma-2 receptor antagonist provided synergism with enzalutamide treatment, showing therapeutic potential to overcome the resistance to current AR-targeted therapies.