Abstract
TRPM2, one member of the transient receptor potential (TRP) protein super-family, is a Ca2+-permeable channel that is activated by oxidative stress and confers susceptibility to cell death. In the human tongue specimens of carcinoma and the tongue carcinoma SCC cell lines, we observed the enhanced expression of TRPM2. By means of the whole-cell electrophysiological recording, the ADPR-induced currents mediated by TRPM2 were recorded in cultured SCC9 cells. Moreover, after H2O2 treatment for 24 hours, the apoptotic number of SCC9 cells was significantly increased. However, the selectively knocked-down TRPM2 with the small interfering RNA technique inhibited the survival and migration of the SCC9 cancer cells, which was independent of the p53-p21 pathway, since the expression of p21 was enhanced after TRPM2 knockdown. Furthermore, the sub-cellular localization of TRPM2 was remarkably different between cancerous and non-cancerous cells. A significant amount of the TRPM2 proteins were located in the nuclei in cancer cells. All these data suggest that TRPM2 is essential for the survival and migration of SCC cancer cells and may be a potential target for the selective treatment of tongue cancer.
Highlights
Member of the TRPM subfamily to be cloned and expressed in many cell types[11]
The present study demonstrates that: 1) TRPM2 channel is highly expressed in squamous cell carcinoma (SCC) cells and tissues, with little or no detectable levels in normal tongue epithelial tissues; 2) TRPM2 is functional in head squamous cell carcinoma (HSCC) cell lines; 3) Activation of TRPM2 by H2O2 increases apoptosis of SCC cells through the p21 and p53 pathway; 4) Inhibition of TRPM2 expression by shRNATRPM2 increases the apoptosis of SCC cells and reduces the migration of SCC cells; 5) The expression of TRPM2 in nuclei is enhanced in SCC cells
Our findings suggest that TRPM2 is involved in the regulation of migration and survival of HSCC cells, and the difference in TRPM2 location may contribute to the different function of TRMP2
Summary
Extracellular signals that activate TRPM2 include oxidative stress, TNFα, amyloid β-peptide, and concanavalin A12–15. Stimulation with these extracellular signals results in production of ADP-ribose (ADPR), which activates TRPM2 by being bound to the TRPM2 COOH-terminal NUDT9-H domain, an ADPR hydrolase[16,17]. TRPM2 is reported to be activated by irradiation via PARP1 activation and be contributing to irreversible loss of salivary gland function[35], which suggests that the disordered expression of TRPM2 may be associated with the occurrence of head squamous cell carcinoma (HSCC). The aim of this study is to assess the expression of TRPM2 channels in human HSCC compared with adjacent normal tissue and papilloma tissue, as well as its functional expression in the highly HSCC cancer cell lines (SCC-9). We further evaluated the role of TRPM2 in the regulation of cell apoptosis and migration, and elucidated the probable mechanism
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