Abstract 5277: Activation of TRPM8 channel suppresses prostate cancer growth and progression

Abstract

Abstract Prostate cancer (PC) is one of the most prevalent male malignancies and a leading cause of cancer-related deaths in men. While androgen-deprivation therapy is successful in the early stages of PC, tumor cells eventually become resistant to its effects. With a median survival of 18 months, the shift to androgen-independent prostate cancer (AIPC) has a poor prognosis. Mechanisms causing this change have yet to be explained, however mounting evidence implicates the loss of transient receptor potential melastatin 8 (TRPM8) as a significant contributor. The prostate epithelium normally expresses the ionotropic receptor TRPM8. Our team has recently shown that testosterone-induced activation of TRPM8 enhances Ca2+ absorption and causes apoptosis. This prompted us to propose that increased TRPM8 activity on the plasma membrane is cytotoxic to PC cells and that TRPM8 internalization is a crucial step in the pathogenesis of PC. We examined the amounts of TRPM8 mRNA in benign tumor and metastatic PC patient datasets. TRPM8 mRNA is initially elevated in the early stages of PC but is increasingly lost during the progression to AIPC. In addition, male and female TRPM8−/− mice exhibited increased serum testosterone levels, heightened AR activity, and activation of cell cycle, invasion, and adhesion-related effectors. In both AR+ and AR− xenograft models, our research reveals that TRPM8 possesses potent antitumor properties. Given this, investigating the in vivo role of TRPM8 in PC has the potential to significantly enhance patient outcomes by preventing progression to the androgen-independent state. Citation Format: Swapna Asuthkar. Activation of TRPM8 channel suppresses prostate cancer growth and progression. [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 5277.