Hypertonicity and Piezo1 Activation Enhance Radiosensitivity of B16 Melanoma

Radiation therapy is widely used for cancer treatment; however, radioresistance remains a major obstacle, particularly in malignant melanoma. In this study, we investigated the effects of hypertonicity and activation of the mechanosensitive ion channel Piezo1 on the radiation response of B16 mouse melanoma cells. Hypertonic conditions significantly impaired radiation-induced DNA damage signaling and/or repair, as evidenced by reduced γH2AX and 53BP1 foci formation, and increased the number of unrepaired DNA damage sites at later time points. Consistently, hypertonicity enhanced radiation-induced reproductive cell death. These effects were attenuated by the Piezo1 inhibitor GsMTx4 and by Piezo1 knockdown, suggesting that Piezo1 partially mediates hypertonicity-induced radiosensitization. Pharmacological activation of Piezo1 using Yoda1 similarly impaired DNA damage responses and enhanced radiation-induced cell death. In addition, the combination of Yoda1 and irradiation significantly suppressed tumor growth in B16 melanoma-bearing mice. Collectively, these findings suggest that hypertonicity and activation of Piezo1 enhance the radiosensitivity of B16 melanoma cells, at least in part through impairment of DNA damage responses, and highlight Piezo1 as a potential target for improving radiotherapy efficacy.