title: Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer.
abstract: The switch of cellular metabolism from mitochondrial respiration to glycolysis is the hallmark of cancer cells and is associated with tumor malignancy. Pyruvate dehydrogenase kinase-1 (PDK1) and PDK3 participate in the metabolic switch of cancer cells; however, the medical significance of PDK1 and PDK3 in cancer progression is not known. Here, we assessed the expression profiles of PDK1 and PDK3 in colorectal cancer. Western blot analysis (n = 74) demonstrated that PDK3 was markedly increased in colon cancer compared to that in adjacent normal tissues, whereas PDK1 was decreased in cancer cells. In addition, PDK3 expression was positively correlated with that of hypoxia inducible factor-1α (HIF-1α) in cancer cells. Further analysis using immunohistochemical staining revealed that PDK3 levels were positively associated with severity of cancer and negatively associated with disease-free survival. In vitro studies using several colon cancer cell lines showed that PDK3 expression was controlled by HIF-1α and contributed to hypoxia-induced increased drug resistance, perhaps explaining why patients with PDK3 overexpression have a greater incidence of treatment failure. Taken together, our findings suggest that PDK3 plays an important role in the metabolic switch and drug resistance of colon cancer and is potentially a novel target for cancer therapy.
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chun-Wun
authors.initials: CW
authors.lastname: Lu
authors.forename: Shau-Chieh
authors.initials: SC
authors.lastname: Lin
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chien
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Lin
authors.forename: Chung-Ta
authors.initials: CT
authors.lastname: Lee
authors.forename: Bo-Wen
authors.initials: BW
authors.lastname: Lin
authors.forename: Jenq-Chang
authors.initials: JC
authors.lastname: Lee
authors.forename: Shaw-Jenq
authors.initials: SJ
authors.lastname: Tsai
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000209:etiology / Q000401:mortality; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; C000631429:PDK1 protein, human; C000631431:PDK3 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases