Abstract 269: TRPM8 as a testosterone receptor: Exploring its role in prostate cancer and male behavior

Abstract The transient receptor potential melastatin 8 (TRPM8) channel has emerged as a critical mediator of testosterone signaling in prostate cancer (PC), influencing both tumor progression and sexually dimorphic behaviors. Our research expands upon TRPM8's role as a testosterone receptor, facilitating calcium influx that modulates cell proliferation and apoptosis in PC cells. Notably, TRPM8 mRNA is overexpressed in androgen-dependent benign PC tumors, but exhibits decreased expression in metastatic tumors, indicating a potential tumor-suppressive function in early-stage PC. This suggests that TRPM8 may serve as a biomarker for disease progression and a therapeutic target in androgen-regulated PC. Moreover, our findings suggest that TRPM8 is involved in sexually dimorphic behavioral responses, particularly in the context of age-dependent testosterone’s effects on male physiology. The absence of TRPM8 has been shown to result in significant alterations in male-specific behaviors, highlighting its role in mediating testosterone's influence on male reproductive and territorial behaviors. The male TRPM8 knock out (TRPM8 KO) mice showed increased serum testosterone when compared to wild type. Together, increased testosterone in the male TRPM8 KO mice is associated with aberrant anxiety and depression-like behavioral responses. This data position TRPM8 as a promising therapeutic target in PC and a key player in the regulation of male-specific behaviors. Further studies are warranted to elucidate the mechanisms by which TRPM8 influences both cancer progression and sexually dimorphic behaviors, particularly in the context of androgen signaling. Citation Format: Erick Benjamin Saldes, Alexandra Erdmier, Jai Velpula, Benny Tom, Timothy E. Koeltzow, Don Vander Griend, Swapna Asuthkar. TRPM8 as a testosterone receptor: Exploring its role in prostate cancer and male behavior [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 269.