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

By J. Son, C. Lyssiotis, Haoqiang Ying, Xiaoxu Wang, Sujun Hua, M. Ligorio, R. Perera, C. Ferrone, Edouard Mullarky, Ng Shyh‐Chang and 8 more. Nature, 2013

1,842 citations recorded by the source corpus.

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.

Subfields: Biochemistry, Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/44b72d6c188ee8d3a88c59bb85e55ca849bef638

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Citations in the corpus

Mitochondrial metabolism and cancer (2017, background): “This involves not only increased uptake of glucose (a fraction of which is redirected to the pentose phosphate pathway (PPP) for nucleic acid synthesis and glutathione reduction) [70], but also the ability to process glutamine oxidatively (for energy production via the Krebs cycle and the ETC) or re”
Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth (2015, neutral): “…+ 8 3+ 1+ + 9 2+ 2+ partial 10 2+/3+ 1+ + 11 3+ 1+/2+ + 12 3+ 1+ + M T C 02 /D A P I C (legend on next page) 546 Molecular Cell 57, 537–551, February 5, 2015 ª2015 Elsevier Inc. et al., 2011; Lock et al., 2011; Rao et al., 2014; Rosenfeldt et al., 2013; Son et al., 2013; Strohecker et al., 2013).”
Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression (2015, background): “reported that in pancreatic cancer, oncogenic KRAS also regulates reprogramming of glutamine metabolism, through the transcriptional upregulation of aspartate transaminase (GOT1) and repression of GLUD1 [115].”
Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer (2017, background): “BRAF TKI + PI3K TKI + EGFR mAbs Phase II 9/28 (32)(147)”
Metabolic Interactions in the Tumor Microenvironment (2017, background): “Based on the observation that pancreatic cancers depend on glutamine metabolism for survival [67, 68], conditioned media from preadipocytes were also found to contain glutamine, which supported pancreatic cancer cell proliferation in glutamine-free growth media [69] (Fig.”
Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. (2015, background): “RAS-driven cells instead rely heavily on glutamine as a TCA carbon source, with glutamine catabolism through the TCA cycle and malic enzyme essential in pancreatic cancer cells (7).”
KRAS: feeding pancreatic cancer proliferation (2014, positive): “Because reliance on GOT1 for the maintenance of redox homeostasis is unique to PDAC, and GOT1 is dispensable in normal cells, this KRAS controlled enzyme could be an exciting therapeutic target [47].”
Glutamine Metabolism in Cancer: Understanding the Heterogeneity (2017, positive): “Nevertheless, tumors that utilize macropinocytosis or uptake extracellular vesicles to acquire glutamine may still require glutaminase and exhibit sensitivity to its inhibition [18,58].”