TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells

Abstract

Extracellular acidity is a hallmark of solid tumors and is associated with metastasis in the tumor microenvironment. Acidic extracellular pH (pH_e) has been found to increase intracellular Ca²⁺ and matrix metalloproteinase-9 (MMP-9) expression by activating NF-κB in the mouse B16 melanoma model. The present study assessed whether TRPM5, an intracellular Ca²⁺-dependent monovalent cation channel, is associated with acidic pH_e signaling and induction of MMP-9 expression in this mouse melanoma model. Treatment of B16 cells with Trpm5 siRNA reduced acidic pH_e-induced MMP-9 expression. Enforced expression of Trpm5 increased the rate of acidic pH_e-induced MMP-9 expression, as well as increasing experimental lung metastasis. This genetic manipulation did not alter the pH_e critical for MMP-9 induction but simply amplified the percentage of inducible MMP-9 at each pH_e. Treatment of tumor bearing mice with triphenylphosphine oxide (TPPO), an inhibitor of TRPM5, significantly reduced spontaneous lung metastasis. In silico analysis of clinical samples showed that high TRPM5 mRNA expression correlated with poor overall survival rate in patients with melanoma and gastric cancer but not in patients with cancers of the ovary, lung, breast, and rectum. These results showed that TRPM5 amplifies acidic pH_e signaling and may be a promising target for preventing metastasis of some types of tumor.