| Summary: | 碩士 === 臺北醫學大學 === 醫學科學研究所 === 98 === Cancer cells have the tendency to increase uptake of glucose, to increase metabolism of glucose to lactate, and are associated with decreases in mitochondrial respiration and adenosine triphosphate (ATP) production, a phenomenon termed the “Warburg effect.” Much attention has focused on the Warburg effect as a target for cancer therapy, including for gliomas. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase that participates in numerous signaling pathways involved in cellular and metabolic processes. Our objective is to study the roles of GSK3β in Warburg effect, which has not been elucidated previously. Specifically, this study focuses on the metabolic roles of GSK3β in glioma cells; we studied the Warburg phenotype in glioma cells using GSK3β activity inhibitor 4-Benzyl-2-methyl-1,2,4- thiadiazolidine-3,5-dione (TDZD-8) and GSK3β clones. The inhibition of GSK3β activity by TDTZ-8 and GSK3βK85R clones and GSK3β expression by shGSK3β clones decreased the expressions of hypoxia inducible factor-1α (HIF1α), glucose transporter-1 (Glut-1), pyruvate dehydrogenase kinase-1(PDK-1) and decreased pyruvate dehydrogenase (PDH) phosphorylation. HIF1α, Glut-1, PDK-1 and PDH are major regulators of cell metabolism and Warburg effect. TDZD-8, GSK3βK85R and shGSK3β clones concurrently decreased glucose uptake, decreased lactate accumulation, increased ATP production and increased oxygen consumption through increasing mitochondria membrane potential in glioma cells. Furthermore, the overexpression of GSK3β in GSK3βWT clones and the constitutive activation of GSK3β activity in GSK3βS9A clones, increased Glut-1, PDK-1 expressions, PDH phosphorylation, glucose uptake and lactate accumulation, but decreased ATP production and decreased oxygen consumption through decreasing mitochondria membrane potential in glioma cells, the opposite effect to the inhibition of GSK3β activity and expression. The increase in ATP production, oxygen consumption and mitochondria membrane potential together with the decrease in lactate accumulation suggests a change in cellular metabolism from anaerobic Warburg phenotype to aerobic usage of glucose. These results suggest that GSK3β may induce the Warburg effect and its inhibition of its activity may decrease this metabolic phenotype. Our findings support a novel role for GSK3β in cancer metabolism, GSK3β may be a possible target for cancer therapy and TDZD-8, which inhibits GSK3β activity, may reverse the Warburg effect.
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