Jackson 2017 Cancer Res
| Jackson LE, Kulkarni S, Wang H, Lu J, Dolezal JM, Bharathi SS, Ranganathan S, Patel MS, Deshpande R, Alencastro F, Wendell SG, Goetzman ES, Duncan AW, Prochownik EV (2017) Genetic dissociation of glycolysis and the TCA cycle affects neither normal nor neoplastic proliferation. Cancer Res 77:5795-807. |
Jackson LE, Kulkarni S, Wang H, Lu J, Dolezal JM, Bharathi SS, Ranganathan S, Patel MS, Deshpande R, Alencastro F, Wendell SG, Goetzman ES, Duncan AW, Prochownik EV (2017) Cancer Res
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.
©2017 American Association for Cancer Research. • Keywords: Hepatoblastoma, Tumor metabolism, Pyruvate dehydrogenase complex • Bioblast editor: Plangger M • O2k-Network Lab: US PA Pittsburgh Goetzman ES
Labels: MiParea: Respiration, Genetic knockout;overexpression
Pathology: Cancer
Organism: Mouse Tissue;cell: Liver Preparation: Intact cells Enzyme: TCA cycle and matrix dehydrogenases
Coupling state: LEAK, OXPHOS Pathway: N, S, NS HRR: Oxygraph-2k
Labels, 2019-08
