Rab GTPases Accelerates GLUT4 Translocation in Colorectal Cancer Progression by Insulin/IGF System

Colorectal cancer is one of the high risks of clinical patients, especially its strong metastatic ability and drug resistance. The components of metabolites or metabolism‐related proteins are individually linked with the prognosis and survival rate of colorectal cancer, respectively. High expression of Insulin‐like growth factor‐1 (IGF‐1) and its receptor (IGF‐1R) in colorectal tumor tissues was studied. Meanwhile, glucose transporter 4 (GLUT4) is an insulin‐response transporter of glucose homeostasis in humans. Several studies reported that GLUT4 translocated from cytoplasm to cell membrane for further serial glycolysis process. Through colorectal tumor tissue array screening, we observed that all class I glucose transporters (GLUT1‐4) were overexpressed in tumors compared to adjacent normal tissues. Moreover, we confirmed that GLUT4 expression levels were highly correlated with IGF1/IGF‐1R by immunohistochemistry and were further associated with survival curve and other clinical parameters of colorectal cancer. We further determined the dynamic switching of GLUT4 is between GLUT4‐storage vesicles (GSVs) in cytoplasm with cell membranes through immunofluorescence assay. Our results indicated that several RABs (RAB8/10/14) bound to GSVs and accelerated GLUT4 translocation, so GLUT4 facilitated the efficiency of glucose transporters in colon cancer cell lines. Furthermore, hyperglycemic conditions prevented cell apoptosis of chemotherapy drug (5‐FU, oxaliplatin and irinotecan) resistance. Therefore, we utilized glucose transporter inhibitors as antagonists in combination with chemotherapy drugs. These results may have clinical implications for chemotherapy strategies to improve colorectal cancer.