Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation
Authors: Laura E Jackson
Sivakama S Bharathi
Sucheta Kulkarni
Huabo Wang
Sarangarajan Ranganathan
Rahul Deshpande
Stacy G Wendell
Frances Alencastro
Andrew W Duncan
James M Dolezal
Edward V Prochownik
Jie Lu
Eric S Goetzman
Mulchand S Patel
Journal: Cancer Research (2017)
Discipline: CLINICAL MEDICINE
Keywords: glycolysis; oxidative phosphorylation; pyruvate dehydrogenase complex; hepatocyte regeneration; malignant transformation
Affiliations: Division of Neonatology, Department of Pediatrics, Children's Hospital of Pittsburgh of The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Division of Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh of The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh of The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Department of Pathology, Children's Hospital of Pittsburgh of The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, New York., Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Department of Pathology, The McGowan Institute for Regenerative Medicine and The Pittsburgh Liver Research Center, The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Division of Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh of The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. ., Department of Microbiology and Molecular Genetics, The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., The University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

Abstract:  Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate's conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic, and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation. In PDC "knockout" (KO) animals, the long-term regenerative potential of hepatocytes was unimpaired, and growth of aggressive experimental hepatoblastomas was only modestly slowed in the face of 80%-90% reductions in AcCoA and significant alterations in the levels of key tricarboxylic acid (TCA) cycle intermediates and amino acids. Overall, oxphos activity in KO livers and hepatoblastoma was comparable with that of control counterparts, with evidence that metabolic substrate abnormalities were compensated for by increased mitochondrial mass. These findings demonstrate that the biochemical link between glycolysis and the TCA cycle can be completely severed without affecting normal or neoplastic proliferation, even under the most demanding circumstances. Cancer Res; 77(21); 5795-807. ©2017 AACR. 

Retracted: No

PubPeer comments:
 Figure 3H appears to have a repeated image *** ![file] ,