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

Hur,Hoon; Xuan,Yi; Kim,Young  Bae; Lee,Gwang; Shim,Wooyoung; Yun,Jisoo; Ham,In-Hye; Han,Sang-Uk

doi:10.3892/ijo.2012.1687

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

Authors:
- Hoon Hur
- Yi Xuan
- Young Bae Kim
- Gwang Lee
- Wooyoung Shim
- Jisoo Yun
- In-Hye Ham
- Sang-Uk Han
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Affiliations: Department of Surgery, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-749, Republic of Korea, Department of Pathology, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-749, Republic of Korea, Institute for Gastric Cancer Mechanism, Ajou University School of Medicine, Suwon, Gyeonggi-do 443-749, Republic of Korea
Published online on: November 6, 2012 https://doi.org/10.3892/ijo.2012.1687
Pages: 44-54
Copyright: © Hur et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

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 various molecules, including pyruvate dehydrogenase kinase-1 (PDK-1), is involved in the altered glucose metabolism associated with gastric cancer prognosis and to assess the role of a therapeutic agent in targeting glucose metabolism in gastric cancer. Immunohistochemistry was performed on gastric cancer tissues obtained from 152 patients who underwent curative resection to assess the expression of hypoxia-inducible factor-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, cellular viability and 5-fluorouracil (5-FU) responses were evaluated before and after treatment with dichloroacetate (DCA), a PDK-1 inhibitor, in the MKN45 and AGS gastric cancer cell lines and in the non-cancerous HEK293 cell line. GLUT-1 and PDK-1 expression was significantly associated with tumor progression, although only PDK-1 expression was an independent prognostic factor for patients who received 5-FU adjuvant treatment. There was no significant difference in cell viability between the HEK293 and gastric cancer cell lines following DCA treatment. However, DCA treatment reduced lactate production and increased responsiveness to 5-FU in MKN45 cells, which expressed high levels of PDK-1 in comparison to the other cell lines. Thus, PDK-1 may serve as a biomarker of poor prognosis in patients with gastric cancer. In addition, PDK-1 inhibitors such as DCA may be considered an additional treatment option for patients with PDK-1-expressing gastric cancers.

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