title: Activation of mitochondrial oxidation by PDK2 inhibition reverses cisplatin resistance in head and neck cancer.
abstract: Dichloroacetate (DCA), an orphan drug that promotes a shift from glycolysis to oxidative phosphorylation, has been repurposed for cancer therapy. The present study investigated whether DCA may overcome cisplatin resistance in head and neck cancer (HNC). Two cisplatin-resistant HNC cell lines (AMC-HN4R and -HN9R), their parental lines, and other human HNC lines were used. The effect of DCA, alone and in combination with cisplatin, was assessed by measuring cell cycle, viability, death, reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨm), and protein expression in preclinical mouse tumor xenograft models. Increased glycolysis correlated with decreased sensitivity to cisplatin and was reduced by DCA. Cisplatin-resistant cells overexpressed pyruvate dehydrogenase kinase 2 (PDK2). DCA induced HNC cell death by decreasing ΔΨm and promoting mitochondrial ROS production. This effect was decreased by the antioxidant N-acetyl-l-cysteine or by inhibition of caspase-mediated apoptosis. Activation of mitochondrial glucose oxidation by DCA eventually activated downstream mitochondrial apoptotic signaling, leading to the death of chemoresistant cancer cells. Therefore, DCA significantly sensitized resistant HNC cells to cisplatin in vitro and in vivo. High glycolysis and PDK2 overexpression are closely linked to cisplatin resistance in HNC cells; the latter can be overcome by DCA.
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: rohjl@amc.seoul.kr.
authors.forename: Jong-Lyel
authors.initials: JL
authors.lastname: Roh
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: Department of Otolaryngology, Gyeongsang National University Hospital School of Medicine, Jinju, Republic of Korea.
authors.forename: Minsu
authors.initials: M
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C000631430:PDK2 protein, human; C000631435:Pdk2 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin
keywords: Cisplatin resistance; Dichloroacetate; Head and neck cancer; Mitochondrial remodeling; PDK2