TRPM4 promotes ErSO-mediated oncosis-like cell death in prostate cancer cells

Advanced and treatment-refractory prostate cancer remains a major clinical challenge and requires new therapeutic strategies. The calcium-activated monovalent cation channel TRPM4 regulates cell volume and has been implicated in cancer progression. TRPM4 was recently identified as a determinant of sensitivity to Acetalax (oxyphenisatin acetate) in triple-negative breast cancer and prostate cancer; however, whether TRPM4 also determines sensitivity to ErSO in prostate cancer cells had not been tested. Here, we investigate the relationship between ErSO, which induces TRPM4-associated cytotoxicity and ERα-positive breast cancer cell death, and TRPM4 expression in prostate cancer models. The Cancer Genome Atlas (TCGA) shows a broad range of TRPM4 expression in prostate cancers, and an integrated analysis of drug-response datasets reveals a positive association between TRPM4 expression and ErSO sensitivity in prostate cancer. Functional studies demonstrate that ErSO induces rapid cellular swelling, nuclear enlargement, and membrane blebbing selectively in TRPM4-high prostate cancer cells, consistent with early oncosis-like morphological responses, whereas TRPM4-low cells are less sensitive. Time-course analyses show a downregulation of TRPM4 following ErSO treatment. Chronic ErSO exposure results in the acquisition of resistance accompanied by loss of TRPM4 expression, and ErSO-resistant cells fail to undergo ErSO-induced morphological changes. Flow cytometry analyses further show that ErSO induces loss of membrane integrity and oncosis-like cell death-associated features in TRPM4-expressing cells. These findings establish TRPM4 as a functional determinant of ErSO responsiveness in prostate cancer cells and support its potential utility as a biomarker of ErSO sensitivity.