Roles of TRPM8 Ion Channels in Cancer: Proliferation, Survival, and Invasion

Abstract

The goal of this article is to provide a critical review of the transient receptor potential melastatin-subfamily member 8 (TRPM8) in cancers, with an emphasis on its roles in cellular proliferation, survival, and invasion. The TRPM8 ion channels regulate Ca²⁺ homeostasis and function as a cellular sensor and transducer of cold temperature. Accumulating evidence has demonstrated that TRPM8 is aberrantly expressed in a variety of malignant solid tumors. Clinicopathological analysis has shown that over-expression of TRPM8 correlates with tumor progression. Experimental data have revealed important roles of TRPM8 channels in cancer cells proliferation, survival, and invasion, which appear to be dependent on the cancer type. Recent reports have begun to reveal the signaling mechanisms that mediate the biological roles of TRPM8 in tumor growth and metastasis. Determining the mechanistic roles of TRPM8 in cancer is expected to elucidate the impact of thermal and chemical stimuli on the formation and progression of neoplasms. Translational research and clinical investigation of TRPM8 in malignant diseases will help exploit these ion channels as molecular biomarkers and therapeutic targets for developing precision cancer medicine.

Keywords: TRPM8; calcium; cancer; cell cycle; invasion; ion channels; proliferation; senescence; survival.

Figure 1

Schematic diagram for the structure of TRPM8 ion channel.

Figure 2

Targeted silencing of TRPM8 induces mitotic abnormalities and replicative arrest in pancreatic cancer cells. The BxPC-3 and PANC-1 cells were transfected with anti-TRPM8 siRNA or non-targeting control siRNA and incubated at 37 °C until analysis. Top panel, phase-contrast micrographs showing that TRPM8-deficient cells contain multiple nuclei and cytoplasmic vacuoles. Bottom panel, DAPI-stained fluorescent micrographs showing that TRPM8-deficient cells contain nuclei being arrested in division consistent with multiple nuclei. For comparison, in both phase-contrast and fluorescent micrographs, control siRNA-transfected cells contain round to oval shaped nuclei with a smooth surface, and no or few cytoplasmic vacuoles.