Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation
Open accessAbstract
Anabolic biosynthesis requires precursors supplied by the Krebs cycle, which in turn requires anaplerosis to replenish precursor intermediates. The major anaplerotic sources are pyruvate and glutamine, which require the activity of pyruvate carboxylase (PC) and glutaminase 1 (GLS1), respectively. Due to their rapid proliferation, cancer cells have increased anabolic and energy demands; however, different cancer cell types exhibit differential requirements for PC- and GLS-mediated pathways for anaplerosis and cell proliferation. Here, we infused patients with early-stage non-small-cell lung cancer (NSCLC) with uniformly 13C-labeled glucose before tissue resection and determined that the cancerous tissues in these patients had enhanced PC activity. Freshly resected paired lung tissue slices cultured in 13C6-glucose or 13C5,15N2-glutamine tracers confirmed selective activation of PC over GLS in NSCLC. Compared with noncancerous tissues, PC expression was greatly enhanced in cancerous tissues, whereas GLS1 expression showed no trend. Moreover, immunohistochemical analysis of paired lung tissues showed PC overexpression in cancer cells rather than in stromal cells of tumor tissues. PC knockdown induced multinucleation, decreased cell proliferation and colony formation in human NSCLC cells, and reduced tumor growth in a mouse xenograft model. Growth inhibition was accompanied by perturbed Krebs cycle activity, inhibition of lipid and nucleotide biosynthesis, and altered glutathione homeostasis. These findings indicate that PC-mediated anaplerosis in early-stage NSCLC is required for tumor survival and proliferation.
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Tracing glucose-derived carbons in human patients and mouse models of glioblastoma and NSCLC reveals that in these contexts the principal source for TCA cycle intermediates is glucose, not glutamine.
“In fact, tracing the fate of glucose-derived carbons in human patients and in mouse models of glioblastoma and non-small cell lung carcinoma (NSCLC) reveals that at least in these tumorigenic contexts, the principal source for the TCA cycle intermediates is not glutamine, but glucose (Maher et al., 2012; Marin-Valencia et al., 2012; Sellers et al., 2015).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Sellers et al., 2015
PDC and PC both catalyze the flux of pyruvate into the TCA cycle, but their metabolic roles do not appear to be interchangeable.
“Although PDC and PC both catalyze the flux of pyruvate into the TCA cycle, their enzymatic activities can be distinguished by stable isotope tracing26,27, and their metabolic roles do not appear to be interchangeable.”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [27]
Many cancers favor PC-mediated anaplerosis.
“Many cancers favor PC-mediated anaplerosis, although the factors that dictate the choice for pyruvate flux between PC and PDC are little studied.27,29,30”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [27]
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- Authors
- Sellers, K., Fox, M. P., Bousamra, M., Slone, S. P., Higashi, R. M., Miller, D. M., Wang, Y., Yan, J., Yuneva, M. O., Deshpande, R., Lane, A. N., & Fan, T. W.-M.
- Affiliations
- University of Louisville (US)
- National Institute for Medical Research (GB)
- University of Kentucky (US)
- Corresponding author
- Lane, Andrew N.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2015-01-20
- Volume
- 125
- Issue
- 2
- Pages
- 687-698
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4319441
- OpenAlex
- W2041729369
- Cited by
- 497
- References
- 44
- Citations by year
- 2026: 20 · 2025: 29 · 2024: 41 · 2023: 23 · 2022: 53 · 2021: 63 · 2020: 57 · 2019: 55 · 2018: 44 · 2017: 53 · 2016: 41 · 2015: 17
- FWCI
- 17.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion)
- Funders
- National Science Foundation (0447479, 0132295)
- University of Louisville (20044)
- Francis Crick Institute (10223)
- National Institutes of Health
- National Cancer Institute (P01CA163223, R01CA118434, R01CA101199, P30CA177558)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK097215)
- National Institute of Environmental Health Sciences (R01ES022191)
- National Center for Research Resources (P20RR018733)
- Office of Experimental Program to Stimulate Competitive Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- pyruvate carboxylase, non-small cell lung cancer, anaplerosis, GLS1, TCA cycle, tumor cell proliferation, 13C-labeled glucose, glutamine metabolism, glutathione homeostasis, lipogenesis, nucleotide synthesis, multinucleation, tumor growth
- MeSH terms
- Animals, Carcinoma, Non-Small-Cell Lung, Citric Acid Cycle, Female, Glucose, Glutathione, Humans, Lung Neoplasms, Male, Neoplasm Proteins, Nucleotides, Pyruvate Carboxylase, Radioactive Tracers, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Cell Proliferation, Lipid Metabolism, Mice, HEK293 Cells
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