Inhibiting Glucose Transporter-1and PI3K/Akt Pathway To Enhance Radiosensitivity Of Laryngeal Carcinoma Hep-2Cell In Vivo

Background:Laryngeal squamous carcinoma is a worldwide common malignant tumor of head and neck. Appropriate radiotherapy, instead of or combined with surgery and/or chemotherapy, helps preserve organ functions and improve life qualityof patients. However, the application of radiotherapy is greatly limited because of radioresistance. Overexpression of glucose transporter protein-1(GLUT-1) and excessive activation of PI3K/Akt signaling pathway had shown to be closely related with the radioresistance of laryngeal cancer. Our article aims to investigate the effect of radiosensitization by inhibiting GLUT-1with antisense oligodeoxynucleotide and specifically inhibiting PI3K/Akt pathway in laryngeal cancer Hep-2cells xenografts.Materials and Methods:Laryngeal cancer xenograft model was established by inoculating nude mice subcutaneously with Hep-2cell suspension. Then, randomly dividing mice into11 groups:control group, GLUT-1AS-ODN group (GLUT-1AS-ODN), Ly294002group, LY294002+GLUT-1AS-ODN group, Wortmannin group, wortmannin+GLUT-1AS-ODN group, lOGy group, LY294002+10Gy group, wortmannin+10Gy group, LY294002+GLUT-1AS-ODN+10Gy groupand wortmannin+GLUT-1AS-ODN+10Gy group. Observed and recorded the volume and weight of every xenograft tumors, calculated tumor inhibition rate and enhanced radio sensitization ratio (E/O), detected the mRNA and protein expression of GLUT-1, p-Akt, PI3K mRNA by real-time RT-PCR and Western blotting, detected cells apoptosis by Tunel technique.Results:Before radiation, antisense GLUT-1, Wortmanin, antisense GLUT-1+Ly294002, antisense GLUT-1+Wortmanin significantly reduced the mRNA and protein expression of GLUT-1, PI3K, p-Akt (p<0.05), promotedlaryngeal cancer cells apoptosis (p<0.05), and inhibitedtumor growth (p<0.05).Ly294002presented a significant pro-apoptotic effect, with inhibited tumor growth but not statistically significant. After lOGy radiation, Ly294002, Wortmanin, antisense GLUT-1+Ly294002, antisense GLUT-1+Wortmanin significantly enhanced the cell-killing effect of X ray radiation (p<0.05). The tumor inhibition rates and E/O values of Ly294002, Wortmanin, antisense GLUT-1+Ly294002, antisense GLUT-1+Wortmanin were respectively3.4%,53.4%,50.0%,43.5%, and2.7,1.8,1.1,1.8.Conclusions:Excessive activation of GLUT-1and PI3K/Akt signaling pathway are associated with the radioresistance of laryngeal cancer. GLUT-1AS-ODN, LY294002, wortmannin increase the radiosensitivity of laryngeal cancer, which is realized by inhibiting themRNA and protein expression of GLUT-1, PI3K, p-Akt, and increasing laryngeal cancer cells apoptosis.