Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway
Open accessAbstract
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.
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Depending on tissue of origin, cancer cells use various routes of glutamine metabolism; some require exogenous glutamine for malignant proliferation, whereas others do not and can synthesize it de novo.
“Furthermore, depending on the tissue of origin, cancer cells use various routes of glutamine metabolism. Some have been shown to require an exogenous glutamine supply for malignant proliferation [71,72], whereas others do not [73] and can synthesize it de novo [74].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [73]
KRAS-dependent upregulation of GOT1/2 in pancreatic cancer facilitates aspartate production for nucleotide biosynthesis and allows NADPH generation via ME1.
“For instance, KRAS-dependent upregulation of Glutamate Oxaloacetate Transaminase 1,2. (GOT) expression in pancreatic cancer facilitates production of aspartate for nucleotide biosynthesis, and allows NADPH generation via ME157,58 (Fig 2).”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [57]
Mouse PDAC tumors driven by mutant Kras experience metabolic alteration and are dependent on glucose and glutamine.
“Mouse PDAC tumors driven by mutant Kras also experience metabolic alteration and are dependent on glucose and glutamine (73, 77).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [77]
Combining glycolysis inhibition with blockade of KRAS effector signaling pathways has shown efficacy in culture and xenograft models.
“combining inhibition of glycolysis with blockade of KRAS effector signaling pathways has shown efficacy in culture and xenograft models197”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [197]
Metabolic inhibition approaches combined with RAS pathway inhibitors have shown strong preclinical data and are currently in clinical trials.
“metabolic inhibition approaches combined with RAS pathway inhibitors have shown strong pre-clinical data and are currently in clinical trials197,224,225”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [197]
Under normal and glucose-replete conditions, transamination is the dominant reaction driving glutamine anaplerosis in cultured cells.
“However, under normal and glucose-replete conditions, transamination is the dominant reaction that drives glutamine anaplerosis in cultured cells (79, 80, 81, 82).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [81]
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Self-citation
- Authors
- 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, Y., Fleming, J. B., Bardeesy, N., Asara, J. M., Haigis, M. C., DePinho, R. A., Cantley, L. C., & Kimmelman, A. C.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Beth Israel Deaconess Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Massachusetts General Hospital (US)
- Harvard University (US)
- Corresponding author
- Cantley, Lewis C.
- Kimmelman, Alec C.
- ORCID
- Venue
- Nature
- Published
- 2013-03-27
- Volume
- 496
- Issue
- 7443
- Pages
- 101-105
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3656466
- OpenAlex
- W2014988241
- Cited by
- 1,990
- References
- 27
- Citations by year
- 2026: 130 · 2025: 143 · 2024: 138 · 2023: 169 · 2022: 193 · 2021: 209 · 2020: 169 · 2019: 162 · 2018: 141 · 2017: 144 · 2016: 152 · 2015: 112 · 2014: 95 · 2013: 31
- FWCI
- 45.68
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-06-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (T32CA009382, R01CA157490, P01CA120964, P01CA117969, P30CA006516)
- National Institute of General Medical Sciences (R01GM056203)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, glutamine metabolism, KRAS, tumor metabolic reprogramming, oxaloacetate, NADPH/NADP+ ratio, redox homeostasis, glutamine deprivation, reactive oxygen species, glutathione, tumor growth
- MeSH terms
- Adenocarcinoma, Aspartate Aminotransferases, Citric Acid Cycle, Glutamate Dehydrogenase, Glutamine, Homeostasis, Humans, Ketoglutaric Acids, Oncogenes, Oxidation-Reduction, Pancreatic Neoplasms, Proto-Oncogene Proteins, Oncogene Protein p21(ras), Proto-Oncogene Proteins p21(ras), Reactive Oxygen Species, ras Proteins, Cell Line, Tumor, Cell Proliferation, Metabolic Networks and Pathways
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