Identification of a natural compound, sesamin, as a novel TRPM8 antagonist with inhibitory effects on prostate adenocarcinoma

Abstract

Transient receptor potential melastatin 8 (TRPM8) is a calcium ion-permeable cation channel that is used as a prognostic marker and therapeutic target for different tumor types. To identify natural selective TRPM8 antagonists, we tested 158 traditional Chinese medicine (TCM) compounds for the ability to inhibit TRPM8. Calcium mobilization assays were used to evaluate the 158 TCM compound components in HEK293 cells stably expressing TRPM8. An identified putative TRPM8 antagonist, sesamin, was further evaluated. Publicly available cancer OMICS data were used to explore the expression of TRPM8, its gene regulatory network, and the survival of patients with prostate adenocarcinoma (PRAD). The cytotoxicity and specificity of sesamin to TRPM8 were tested in HEK293/TRPM8 cells. The effect of sesamin on cell proliferation in PRAD cell lines was assessed. Sesamin selectively inhibited TRPM8 in HEK293/TRPM8 cells (IC50: 9.78 μM), and a molecular docking study confirmed the binding of sesamin to TRPM8. TRPM8 was highly overexpressed in PRAD, and high TRPM8 expression was associated with poor survival of PRAD patients. Functional network analysis suggested that TRPM8 has key effects on proliferation, survival, and invasion of prostate cancer cells. Cell proliferation assays supported these findings and showed that sesamin inhibited the proliferation of PRAD cell lines DU145 and LNCaP cells. These data revealed that abnormal TRPM8 expression is associated with PRAD and that sesamin is a new anti-PRAD candidate drug, exerting inhibitory effects on TRPM8.

Keywords: Antagonist; Calcium mobilization; Prostate adenocarcinoma; Sesamin; Transient receptor potential melastatin 8.