Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway

Jaekyoung Son, Costas A. Lyssiotis, Haoqiang Ying, Xiaoxu Wang, Sujun Hua, Matteo Ligorio, Rushika M. Perera, Cristina R. Ferrone, Edouard Mullarky, Ng Shyh-Chang, Ya'An Kang, Jason B. Fleming, Nabeel Bardeesy, John M. Asara, Marcia C. Haigis, Ronald A. Depinho, Lewis C. Cantley, Alec C. Kimmelman

Research output: Contribution to journalArticle

838 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)101-105
Number of pages5
JournalNature
Volume496
Issue number7443
DOIs
StatePublished - Apr 4 2013

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway'. Together they form a unique fingerprint.

  • Cite this

    Son, J., Lyssiotis, C. A., Ying, H., Wang, X., Hua, S., Ligorio, M., Perera, R. M., Ferrone, C. R., Mullarky, E., Shyh-Chang, N., Kang, YA., Fleming, J. B., Bardeesy, N., Asara, J. M., Haigis, M. C., Depinho, R. A., Cantley, L. C., & Kimmelman, A. C. (2013). Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature, 496(7443), 101-105. https://doi.org/10.1038/nature12040