title: Expression of pyruvate dehydrogenase kinase-1 in gastric cancer as a             potential therapeutic target.
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.
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Hoon
authors.initials: H
authors.lastname: Hur
authors.forename: Yi
authors.initials: Y
authors.lastname: Xuan
authors.forename: Young Bae
authors.initials: YB
authors.lastname: Kim
authors.forename: Gwang
authors.initials: G
authors.lastname: Lee
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Shim
authors.forename: Jisoo
authors.initials: J
authors.lastname: Yun
authors.forename: In-Hye
authors.initials: IH
authors.lastname: Ham
authors.forename: Sang-Uk
authors.initials: SU
authors.lastname: Han
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D018279:Carcinoma, Signet Ring Cell / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D002470:Cell Survival / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007124:Immunoenzyme Techniques; D019344:Lactic Acid / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D015996:Survival Rate; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019344:Lactic Acid; D003999:Dichloroacetic Acid; D006593:Hexokinase; D017346:Protein Serine-Threonine Kinases; D005947:Glucose; D005472:Fluorouracil