TRPC5 mediates TMZ resistance in TMZ-resistant glioblastoma cells via NFATc3-P-gp pathway.

P-glycoprotein (P-gp) acts as a pump to transport cytotoxic drugs out of cells and is upregulated in cancer cells. Suppressing the expression of P-gp is an effective strategy to overcome multidrug resistance in cancer chemotherapy. Temozolomide (TMZ) is the recommended drug for the standard treatment of patients with glioblastoma, but its clinical application is restricted due to drug resistance. Transient receptor potential channel-5 (TRPC5), a Ca-permeable channel, has been attributed to a different drug resistance mechanism except DNA repair system; therefore, we aimed to elucidate the mechanism regarding the role of TRPC5 in TMZ resistance. TRPC5 and P-glycoprotein (P-gp) are upregulated in TMZ-resistant glioblastoma cell lines. The downregulation of TRPC5 inhibited P-gp expression and led to a significant reversal of TMZ resistance in TMZ-resistant cell lines. TRPC5-siRNA restricted the growth of tumour xenografts in an athymic nude mouse model of TMZ-resistant cells. In specimens from patients with recurrent glioblastoma, TRPC5 was found to be highly expressed, accompanied by the upregulation of P-gp expression. The nuclear factor of activated T cell isoform c3 (NFATc3), which acts as a transcriptional factor, bridges TRPC5 activity to P-gp induction. In conclusion, these results demonstrate the functional role of the TRPC5-NFATc3-P-gp signalling pathway in TMZ resistance in glioblastoma cells.