Different Effect of 5-Fluorouracil on Expression of Genes Related to Aerobic Glycolysis According to Chemoresponsiveness in Gastric Cancer Cells

Abstract

5-fluorouracil(5-FU) is one of the chemotherapeutic agents that has been used widely in gastric cancer. However, the responsiveness of 5-FU has been limited for several gastric cancer patients, and this limitation is believed to be caused by chemoresistance. To date, the mechanism of chemoresistance for gastric cancer is not well known. Herein, we made a hypothesis that the sensitivity of gastric cancer to 5-FU might be related to the aerobic glycolysis pathway which depends on the hypoxia-inducible factor 1α (HIF 1α).

I investigated HIF1α expression and responsiveness to 5-FU in two different types of gastric cancer cells (MKN45, SNU216). In addition, we checked the change of the expressions of aerobic glycolysis related genes (GLUT1, PGK1 and PDK1), and the rate of glucose uptake in those cells.

HIF 1α was highly expressed in SNU216, and the responsiveness of SNU216 to 5-FU was lower than it of MKN45. The expressions of glucose transporter 1(GLUT1), phospho-glycerate kinase 1(PGK1) and pyruvate dehydrogenase kinase 1(PDK1) genes were dose- dependently decreased in MKN45 after 5-FU treatment, but not in SNU216. The rate of glucose uptake in MKN45 was significantly inhibited by increasing the dose of 5-FU.

The responsiveness of gastric cancer cell to 5-FU is dependent on HIF 1α expression, and the effectiveness of 5-FU on glucose metabolism is contingent upon the expression of HIF 1α. Therefore, the expression of HIF 1α or early change of glucose metabolism might be a marker of chemosensitivity in gastric cancer.