title: Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.
abstract: Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose and glutamine. Most of the remaining metabolites taken up by proliferating cells are not catabolized, but instead are used as building blocks during anabolic macromolecular synthesis. Investigations of phosphoinositol 3-kinase (PI3K) and its downstream effector AKT have confirmed that these oncogenes play a direct role in stimulating glucose uptake and metabolism, rendering the transformed cell addicted to glucose for the maintenance of survival. In contrast, less is known about the regulation of glutamine uptake and metabolism. Here, we report that the transcriptional regulatory properties of the oncogene Myc coordinate the expression of genes necessary for cells to engage in glutamine catabolism that exceeds the cellular requirement for protein and nucleotide biosynthesis. A consequence of this Myc-dependent glutaminolysis is the reprogramming of mitochondrial metabolism to depend on glutamine catabolism to sustain cellular viability and TCA cycle anapleurosis. The ability of Myc-expressing cells to engage in glutaminolysis does not depend on concomitant activation of PI3K or AKT. The stimulation of mitochondrial glutamine metabolism resulted in reduced glucose carbon entering the TCA cycle and a decreased contribution of glucose to the mitochondrial-dependent synthesis of phospholipids. These data suggest that oncogenic levels of Myc induce a transcriptional program that promotes glutaminolysis and triggers cellular addiction to glutamine as a bioenergetic substrate.
authors.affiliation: Department of Cancer Biology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Wise
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.forename: Anthony
authors.initials: A
authors.lastname: Mancuso
authors.forename: Nabil
authors.initials: N
authors.lastname: Sayed
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Zhang
authors.forename: Harla K
authors.initials: HK
authors.lastname: Pfeiffer
authors.forename: Ilana
authors.initials: I
authors.lastname: Nissim
authors.forename: Evgueni
authors.initials: E
authors.lastname: Daikhin
authors.forename: Marc
authors.initials: M
authors.lastname: Yudkoff
authors.forename: Steven B
authors.initials: SB
authors.lastname: McMahon
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D000818:Animals; D002460:Cell Line; D004734:Energy Metabolism / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose