Elevated expression of TrpC5 and GLUT1 is associated with chemoresistance in colorectal cancer

Abstract

Reprogramming of energy metabolism (aerobic glycolysis) is thought to play an essential role in cancer. Compared to oxidative phosphorylation, aerobic glycolysis consumes more glucose through the upregulation of glucose transporters, notably glucose transporter 1 (GLUT1). Elevated glycolysis occurs in chemoresistant cancer cells, but the detailed mechanism is not well understood. The upregulation of the Ca2+-permeable transient receptor potential channel 5 (TrpC5) activates the Wnt/β-catenin signaling pathway in 5-fluorouracil (5-Fu)-resistant human colorectal cancer (CRC) HCT-8 (HCT-8/5-Fu) cells. In the present study, TrpC5 was overexpressed at the mRNA and protein levels along with GLUT1 in HCT-8/5-Fu cells. Suppression of TrpC5 expression with a TrpC5-specific shRNA reduced the induction of GLUT1 in the HCT-8 cells. The inhibition of the Wnt/β-catenin signaling pathway with XAV939 resulted in a decreased GLUT1 and nuclear c-Myc expression. Further study using clinical specimens validated the positive correlation between TrpC5 and GLUT1 protein levels and showed that a high TrpC5/GLUT1 expression was significantly correlated with chemoresistance. Taken together, we demonstrated the essential role of TrpC5 in GLUT1 induction and revealed that a high TrpC5/GLUT1 expression is associated with chemoresistance in human CRC.