Anti-cancer agent piperlongumine is an inhibitor of transient receptor potential melastatin 7 channel in oral squamous cell carcinoma

To elucidate the association between the anticancer activities of piperlongumine (PL) and its potential target, transient receptor potential melastatin 7 channel (TRPM7), in oral squamous cell carcinoma (OSCC). The expression levels and electrical characteristics of TRPM7 as well as cell viability in response to various PL treatments were investigated in the OSCC cell line Cal27. PL treatment resulted in a concentration- and time-dependent reduction in TRPM7 mRNA and protein expression in Cal27 cells. Furthermore, PL treatment inhibited TRPM7-like rectifying currents in Cal27 cells; however, this inhibition was less effective than that of the TRPM7 antagonist waixenicin A. Rapid perfusion and washout experiments revealed an immediate inhibitory effect of PL on TRPM7-like currents. The antagonistic effect of PL occurred within 1 min and was not completely reversed following washout. Notably, the extracellular Ca2+ concentration still influenced PL-induced changes in the TRPM7-like current, indicating that PL can directly but gently antagonize the TRPM7 channel. Functional changes in TRPM7 correlated with the observed antiproliferative and cytotoxic effects of PL in Cal27 cells. These findings suggest that PL exhibits potent inhibitory effects on TRPM7 and exerts its anti-cancer effects by downregulating TRPM7 expression and antagonizing channel currents.