title: c-Myc programs fatty acid metabolism and dictates acetyl-CoA abundance and fate.
abstract: myc(-/-) rat fibroblasts (KO cells) differ from myc(+/+) (WT) cells and KO cells with enforced Myc re-expression (KO-Myc cells) with respect to mitochondrial structure and function, utilization of glucose and glutamine as energy-generating substrates, and ATP levels. Specifically, KO cells demonstrate low levels of glycolysis and oxidative phosphorylation, dysfunctional mitochondria and electron transport chain complexes, and depleted ATP stores. We examined here how these cells adapt to their energy-deficient state and how they differ in their uptake and utilization of long- and medium-chain fatty acids such as palmitate and octanoate, respectively. Metabolic tracing of these molecules showed that KO cells preferentially utilize them as β-oxidation substrates and that, rather than directing them into phospholipids, preferentially store them as neutral lipids. KO cell transcriptional profiling and functional assays revealed a generalized up-regulation of pathways involved in fatty acid transport and catabolism as well as evidence that these cells attempt to direct acetyl-CoA into the tricarboxylic acid (TCA) cycle for ATP production rather than utilizing it for anabolic purposes. Additional evidence to support this idea included the finding that AMP-dependent protein kinase was constitutively activated in KO cells. The complex control of pyruvate dehydrogenase, which links glycolysis to the TCA cycle, was also maximized to ensure the conversion of pyruvate to acetyl-CoA. Despite these efforts to maximize acetyl-CoA for energy-generating purposes, its levels remained chronically low in KO cells. This suggests that tumor cells with Myc deregulation might be susceptible to novel therapies that limit acetyl-CoA availability.
authors: From the Divisions of Hematology/Oncology and.
authors: Lia R
authors: LR
authors: Edmunds
authors: From the Divisions of Hematology/Oncology and.
authors: Lokendra
authors: L
authors: Sharma
authors: From the Divisions of Hematology/Oncology and.
authors: Audry
authors: A
authors: Kang
authors: From the Divisions of Hematology/Oncology and.
authors: Jie
authors: J
authors: Lu
authors: Medical Genetics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania 15224.
authors: Jerry
authors: J
authors: Vockley
authors: Medical Genetics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania 15224.
authors: Shrabani
authors: S
authors: Basu
authors: Medical Genetics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania 15224.
authors: Radha
authors: R
authors: Uppala
authors: Medical Genetics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania 15224.
authors: Eric S
authors: ES
authors: Goetzman
authors: Medical Genetics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania 15224.
authors: Megan E
authors: ME
authors: Beck
authors: the Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Mt. Sinai School of Medicine, New York, New York 10029.
authors: Donald
authors: D
authors: Scott
authors: From the Divisions of Hematology/Oncology and the Department of Microbiology and Molecular Genetics, The University of Pittsburgh, Pittsburgh, Pennsylvania 15219, and the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15224 procev@chp.edu.
authors: Edward V
authors: EV
authors: Prochownik
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D006019:Glycolysis; D006801:Humans; D007658:Ketone Oxidoreductases / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005227:Fatty Acids; D016271:Proto-Oncogene Proteins c-myc; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+); D055372:AMP-Activated Protein Kinases
keywords: AMP-activated Kinase (AMPK); Electron Transfer Complex; Mitochondria; Pyruvate Dehydrogenase Complex (PDC); Tricarboxylic Acid Cycle (TCA Cycle) (Krebs cycle); Warburg Effect