title: Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.
abstract: Cancer cells have metabolic dependencies that distinguish them from their normal counterparts. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes. Indeed, the spectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumour growth. Whereas most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP(+) ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumours.
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Jaekyoung
authors.initials: J
authors.lastname: Son
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Wang
authors.forename: Sujun
authors.initials: S
authors.lastname: Hua
authors.forename: Matteo
authors.initials: M
authors.lastname: Ligorio
authors.forename: Rushika M
authors.initials: RM
authors.lastname: Perera
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.forename: Edouard
authors.initials: E
authors.lastname: Mullarky
authors.forename: Ng
authors.initials: N
authors.lastname: Shyh-Chang
authors.forename: Ya'an
authors.initials: Y
authors.lastname: Kang
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001219:Aspartate Aminotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002952:Citric Acid Cycle; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics; D010084:Oxidation-Reduction; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D017382:Reactive Oxygen Species / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D007656:Ketoglutaric Acids; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D005973:Glutamine; D005969:Glutamate Dehydrogenase; C561840:GLUD1 protein, human; D001219:Aspartate Aminotransferases; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
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