Inhibition of Sirolimus on the growth of pancreatic carcinoma and its effect on the expression of glucose transporter and hexokinase Ⅱ

Abstract

To investigate whether Sirolimus could affect the glycolytic catabolism pathways of pancreatic carcinoma through the control of hypoxia induced factor (HIF-1α) to inhibit the growth of tumor, and explore the potential mechanism of targeting the signaling pathways of mTOR for the treatment of pancreatic carcinoma. Sirolimus was applied to treat the pancreatic carcinoma in nude mice orthotopic transplantation model, its difference with the control group was compared; RT-PCR and Western blot were used to measure the mRNA and protein expression of mTOR, HIF-1α, Glucose carrier protein 1 (GLUT-1) and Hexokinase Ⅱ (HK-Ⅱ), respectively; the changes of activity of HK-Ⅱ in the tumor was determined. The tumor mass of the control group (1.97±0.21)g was significantly larger than that of the Sirolimus group (0.38±0.10)g (P<0.01), and the volume of the control group (1.40±0.15) mm(3) was significantly larger than that of the Sirolimus group (0.27±0.07) mm(3) (P<0.01). The expressions of mTOR, GLUT-1 and HK-Ⅱ mRNA in the control group were higher than those of the Sirolimus group (P<0.05), while no significant change was observed in the expression of HIF-1α (P>0.05); the expressions of p-mTOR, HIF-1α, GLUT-1 and HK-Ⅱ proteins in the control group were higher than those of the Sirolimus group (P<0.05). The activity of HK-Ⅱ in the control group was higher than that of the Sirolimus group (P<0.05). Sirolimus could affect the expression of GLUT-1 and HK-Ⅱ in pancreatic carcinoma through the effects of HIF-1α to inhibit tumor growth, indicating that blocking the mTOR pathway could control the glycolytic metabolism pathways of pancreatic carcinoma, which may become the new strategy for the treatment of pancreatic carcinoma.