title: Hypoxic repression of pyruvate dehydrogenase activity is necessary for metabolic reprogramming and growth of model tumours.
abstract: Tumour cells fulfil the bioenergetic and biosynthetic needs of proliferation using the available environmental metabolites. Metabolic adaptation to hypoxia causes decreased mitochondrial function and increased lactate production. This work examines the biological importance of the hypoxia-inducible inhibitory phosphorylations on the pyruvate dehydrogenase E1α subunit. Pancreatic cancer cell lines were genetically manipulated to alter the net phosphorylation of PDH E1α through reduced kinase expression or enhanced phosphatase expression. The modified cells were tested for hypoxic changes in phosphorylated E1α, mitochondrial metabolism and growth as xenografted tumours. Even though there are four PDHK genes, PDHK1 is essential for inhibitory PDH phosphorylation of E1α at serine 232, is partially responsible for modification of serines 293 and 300, and these phosphorylations are necessary for model tumour growth. In order to determine the clinical relevance, a cohort of head and neck cancer patient biopsies was examined for phosphorylated E1α and expression of PDHK1. Patients with detectable 232 phosphorylation or expression of PDHK1 tend to have worse clinical outcome. These data show that PDHK1 activity is unique and non-redundant in the family of PHDK enzymes and a PDHK1 specific inhibitor would therefore have anti-cancer activity with reduced chance of side effects from inhibition of other PDHKs.
authors: Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, 84505, Slovak Republic.
authors: Tereza
authors: T
authors: Golias
authors: Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center and Wexner Medical Center, Columbus OH 43210, USA.
authors: Ioanna
authors: I
authors: Papandreou
authors: Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center and Wexner Medical Center, Columbus OH 43210, USA.
authors: Ramon
authors: R
authors: Sun
authors: Department of Otolaryngology, Ohio State University Comprehensive Cancer Center and Wexner Medical Center, Columbus OH 43210, USA.
authors: Bhavna
authors: B
authors: Kumar
authors: Department of Biomedical Informatics, Center for Biostatistics, Ohio State University Comprehensive Cancer Center and Wexner Medical Center, Columbus OH 43210, USA.
authors: Nicole V
authors: NV
authors: Brown
authors: Department of Pathology, Ohio State University Comprehensive Cancer Center and Wexner Medical Center, Columbus OH 43210, USA.
authors: Benjamin J
authors: BJ
authors: Swanson
authors: Department of Pathology, University of Pittsburg, Pittsburg PA 15213, USA.
authors: Reetesh
authors: R
authors: Pai
authors: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors: Diego
authors: D
authors: Jaitin
authors: Department of Radiation Oncology, Stanford University School of Medicine, Stanford CA 94305, USA.
authors: Quynh-Thu
authors: QT
authors: Le
authors: Department of Otolaryngology, Ohio State University Comprehensive Cancer Center and Wexner Medical Center, Columbus OH 43210, USA.
authors: Theodoros N
authors: TN
authors: Teknos
authors: Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center and Wexner Medical Center, Columbus OH 43210, USA.
authors: Nicholas C
authors: NC
authors: Denko
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D011768:Pyruvate Dehydrogenase Complex