TRPML1 inhibitor ML-SI1 suppresses prostate cancer through dual regulation of androgen receptor and polyamine metabolism.

Background: Prostate cancer (PCa) is the second leading cause of cancer-related death in men worldwide, with metastasis and drug resistance representing major drivers of mortality. Transient receptor potential mucolipin 1 (TRPML1), a member of the transient receptor potential channel superfamily, is associated with several malignancies; however, its role in PCa remains unclear. Methods: TRPML1 expression in PCa is analyzed using public datasets from The Cancer Genome Atlas, Human Protein Atlas, and Cancer Cell Line Encyclopedia. Functional studies are performed in prostate cancer cell lines, particularly LNCaP and 22Rv1, using the TRPML1 inhibitor ML-SI1 and TRPML1-knockout models. Cell proliferation, cell cycle distribution, migration, and invasion are assessed using colorimetric cell viability assays, flow cytometry, and Transwell assays. Transcriptomic analysis, quantitative real-time PCR, western blotting, and spermine measurement are performed to investigate the underlying mechanisms. Results: TRPML1 expression is elevated in PCa tissues compared to adjacent normal tissues. In LNCaP cells, ML-SI1 reduces cell viability and migration and induces G0/G1-phase arrest, whereas in 22Rv1 cells, it exerts limited effects on cell viability and cell-cycle distribution but reduces migration and invasion. ML-SI1 reduces androgen receptor (AR) protein stability and spermine levels in LNCaP cells, whereas increased spermine levels are observed in 22Rv1 cells at 24 h. Conclusions: