Cited by 500Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerCancer, Lipids, and Metabolism

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Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation

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Sellers, Katherine, Fox, Matthew P., Bousamra, Michael, Slone, Stephen P., Higashi, Richard M., Miller, Donald M., Wang, Yali, Yan, Jun, Yuneva, Mariia O., Deshpande, Rahul, Lane, Andrew N., Fan, Teresa W.-M.·2015·Journal of Clinical Investigation

DOI 10.1172/jci72873PMC PMC4319441

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Abstract

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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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: Higashi, Richard M.
Miller, Donald M.
Wang, Yali
Yan, Jun
Yuneva, Mariia O.
Lane, Andrew N.
Fan, Teresa W.-M.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2015-01-20
Volume: 125
Issue: 2
Pages: 687-698
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci72873
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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Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation

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