Activation of mitochondrial oxidation by PDK2 inhibition reverses cisplatin resistance in head and neck cancer

• Published in: Cancer letters Vol. 371; no. 1; pp. 20 - 29
• Main Authors: Roh, Jong-Lyel, Park, Jin Young, Kim, Eun Hye, Jang, Hye Jin, Kwon, Minsu
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.02.2016; Elsevier Limited
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Bioenergetics; Cancer therapies; Caspase Inhibitors - pharmacology; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Cisplatin - pharmacology; Cisplatin resistance; Conflicts of interest; Cytotoxicity; Dehydrogenases; Dichloroacetate; Dichloroacetic Acid - pharmacology; Dose-Response Relationship, Drug; Drug resistance; Drug Resistance, Neoplasm - drug effects; Enzyme Inhibitors - pharmacology; Glucose; Glycolysis - drug effects; Head & neck cancer; Head and neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; Hematology, Oncology and Palliative Medicine; Humans; Kinases; Male; Membrane Potential, Mitochondrial - drug effects; Metabolism; Mice, Inbred BALB C; Mice, Nude; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondria - pathology; Mitochondrial remodeling; Oxidation; Oxidation-Reduction; PDK2; Phosphorylation; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Radiation therapy; Reactive Oxygen Species - metabolism; RNA Interference; Time Factors; Transfection; Xenograft Model Antitumor Assays; pyruvate dehydrogenase isoform E1α; 2′,7′-dichlorofluorescein diacetate; OXPHOS; PARP; Mitochondrial remodeling; short interfering RNA; MTV; dichloroacetate; TUNEL; ΔΨm; reactive oxygen species; 18F-fluorodeoxyglucose; cisplatin; PDK2; N-acetyl- l-cysteine; metabolic tumor volume; DCA; head and neck cancer; poly(ADP-ribose) polymerase; mitochondrial membrane potential; siRNA; 18F-FDG; oxidative phosphorylation; standardized uptake value; NAC; CDDP; PDHE1α; pyruvate dehydrogenase kinase 2; SUV; ROS; terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; DCF-DA; Cisplatin resistance; HNC; positron emission tomography; PET; Dichloroacetate; Head and neck cancer
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2015.11.023

Highlights • Increased glycolysis and PDK2 overexpression in HNC cells were correlated with decreased sensitivity to cisplatin. • Dichloroacetate (DCA) shifted cellular bioenergetics from glycolysis to mitochondrial oxidative phosphorylation. • DCA induced ROS accumulation and activated downstream mitochondrial apoptotic signaling in HNC cells. • DCA significantly reversed cisplatin resistance in HNC cells in vitro and in vivo.