Expression of pyruvate dehydrogenase kinase-1 in gastric cancer as a potential therapeutic target

In contrast to mitochondria in healthy cells, which utilize oxidative phosphorylation,malignant cells undergo elevated glycolysis for energy production using glucose.The objectives of this study were to evaluate whether the expression of variousmolecules, including pyruvate dehydrogenase kinase-1 (PDK-1), is involved in thealtered glucose metabolism associated with gastric cancer prognosis and to assessthe role of a therapeutic agent in targeting glucose metabolism in gastric cancer.Immunohistochemistry was performed on gastric cancer tissues obtained from 152patients who underwent curative resection to assess the expression of hypoxia-induciblefactor-1α (HIF-1α), glucose transporter-1 (GLUT-1), hexokinase-2 (HK-2) and PDK-1.In an in vitro analysis, the lactate production and glucose uptake levels, cellularviability and 5-fluorouracil (5-FU) responses were evaluated before and aftertreatment with dichloroacetate (DCA), a PDK-1 inhibitor, in the MKN45 and AGSgastric cancer cell lines and in the non-cancerous HEK293 cell line. GLUT-1 andPDK-1 expression was significantly associated with tumor progression, althoughonly PDK-1 expression was an independent prognostic factor for patients who received5-FU adjuvant treatment. There was no significant difference in cell viabilitybetween the HEK293 and gastric cancer cell lines following DCA treatment. However,DCA treatment reduced lactate production and increased responsiveness to 5-FUin MKN45 cells, which expressed high levels of PDK-1 in comparison to the othercell lines. Thus, PDK-1 may serve as a biomarker of poor prognosis in patientswith gastric cancer. In addition, PDK-1 inhibitors such as DCA may be consideredan additional treatment option for patients with PDK-1-expressing gastric cancers.