The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197
Warburg, O. (1956) · Science · doi:10.1126/science.123.3191.309 · Cited by 13,425
Fundamentals of Biostatistics.
(1969) · Annals of Internal Medicine · doi:10.7326/0003-4819-70-4-873 · Cited by 4,573
DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., & Thompson, C. B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709747104 · Cited by 2,622
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Possemato, R., Marks, K. M., Shaul, Y. D., Pacold, M. E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.-K., Jang, H. G., Jha, A. K., et al. (2011) · Nature · doi:10.1038/nature10350 · Cited by 1,683
Reductive carboxylation supports growth in tumour cells with defective mitochondria
Mullen, A. R., Wheaton, W. W., Jin, E. S., Chen, P.-H., Sullivan, L. B., Cheng, T., Yang, Y., Linehan, W. M., Chandel, N. S., & DeBerardinis, R. J. (2012) · Nature · doi:10.1038/nature10642 · Cited by 1,328
Oncogenic alterations of metabolism
Dang, C. V., & Semenza, G. L. (1999) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(98)01344-9 · Cited by 1,106
Glucose-Independent Glutamine Metabolism via TCA Cycling for Proliferation and Survival in B Cells
Le, A., Lane, A. N., Hamaker, M., Bose, S., Gouw, A., Barbi, J., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Zhang, H., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2011.12.009 · Cited by 1,095
Self-citationWise, D. R., Ward, P. S., Shay, J. E. S., Cross, J. R., Gruber, J. J., Sachdeva, U. M., Platt, J. M., DeMatteo, R. G., Simon, M. C., & Thompson, C. B. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117773108 · Cited by 975
Multifaceted roles of glycolytic enzymes
Kim, J., & Dang, C. V. (2005) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2005.01.005 · Cited by 692
Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells
Yuneva, M., Zamboni, N., Oefner, P., Sachidanandam, R., & Lazebnik, Y. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200703099 · Cited by 690
Self-citationThe metabolic profile of tumors depends on both the responsible genetic lesion and tissue type
Yuneva, M. O., Fan, T. W. M., Allen, T. D., Higashi, R. M., Ferraris, D. V., Tsukamoto, T., Matés, J. M., Alonso, F. J., Wang, C., Seo, Y., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2011.12.015 · Cited by 639
Self-citationHertz, L., Peng, L., & Dienel, G. A. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600343 · Cited by 587
Marin-Valencia, I., Yang, C., Mashimo, T., Cho, S., Baek, H., Yang, X.-L., Rajagopalan, K. N., Maddie, M., Vemireddy, V., Zhao, Z., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.05.001 · Cited by 529
Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1
Seltzer, M. J., Bennett, B. D., Joshi, A. D., Gao, P., Thomas, A. G., Ferraris, D. V., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Rabinowitz, J. D., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1666 · Cited by 528
Xie, H., Hanai, J.-I., Ren, J.-G., Kats, L., Burgess, K., Bhargava, P., Signoretti, S., Billiard, J., Duffy, K. J., Grant, A., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.003 · Cited by 516
Self-citationHaem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase
Frezza, C., Zheng, L., Folger, O., Rajagopalan, K. N., MacKenzie, E. D., Jerby, L., Micaroni, M., Chaneton, B., Adam, J., Hedley, A., et al. (2011) · Nature · doi:10.1038/nature10363 · Cited by 503
Pyruvate carboxylase is required for glutamine-independent growth of tumor cells
Cheng, T., Sudderth, J., Yang, C., Mullen, A. R., Jin, E. S., Matés, J. M., & DeBerardinis, R. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016627108 · Cited by 475
Fan, T. W. ‐., Lane, A. N., Higashi, R. M., Farag, M. A., Gao, H. T., Bousamra, M., & Miller, D. M. (2009) · Molecular Cancer · doi:10.1186/1476-4598-8-41 · Cited by 438
Self-citationMetabolism of [U‐ 13 C]glucose in human brain tumors in vivo
Maher, E. A., Marin‐Valencia, I., Bachoo, R. M., Mashimo, T., Raisanen, J., Hatanpaa, K. J., Jindal, A., Jeffrey, F. M., Choi, C., Madden, C., et al. (2012) · NMR in Biomedicine · doi:10.1002/nbm.2794 · Cited by 341
Guppy, M., Leedman, P. J., XinLin, Z. U., & Russell, V. R. (2002) · Biochemical Journal · doi:10.1042/bj3640309 · Cited by 262
LOBO, C., RUIZ-BELLIDO, M. A., ALEDO, J. C., MÁRQUEZ, J., NÚÑEZ DE CASTRO, I., & ALONSO, F. J. (2000) · Biochemical Journal · doi:10.1042/bj3480257 · Cited by 151
Mazurek, S., & EIGENBRODT, E. (2003) · PubMed · Cited by 136
State of the art direct 13 C and indirect 1 H‐[ 13 C] NMR spectroscopy in vivo . A practical guide
de Graaf, R. A., Rothman, D. L., & Behar, K. L. (2011) · NMR in Biomedicine · doi:10.1002/nbm.1761 · Cited by 117
Stable isotope resolved metabolomics of lung cancer in a SCID mouse model
Fan, T. W. ‐., Lane, A. N., Higashi, R. M., & Yan, J. (2010) · Metabolomics · doi:10.1007/s11306-010-0249-0 · Cited by 115
Self-citationNMR-based metabolomics: translational application and treatment of cancer.
Serkova, N. J., Spratlin, J. L., & Eckhardt, S. G. (2007) · PubMed · Cited by 96
Isotopomer analysis of lipid biosynthesis by high resolution mass spectrometry and NMR
Lane, A. N., Fan, T. W. ‐., Xie, Z., Moseley, H., & Higashi, R. M. (2009) · Analytica Chimica Acta · doi:10.1016/j.aca.2009.08.032 · Cited by 90
Self-citationLane, A. N., Fan, T. W. ‐., Bousamra, M., Higashi, R. M., Yan, J., & Miller, D. M. (2011) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2010.0088 · Cited by 87
Self-citationGlucose and glutamine metabolism in C6 glioma cells studied by carbon 13 NMR
Portais, J., Voisin, P. J., Merle, M., & Canioni, P. (1996) · Biochimie · doi:10.1016/0300-9084(96)89500-9 · Cited by 76
Fan, T. W. ‐., Kucia, M., Jankowski, K., Higashi, R. M., Ratajczak, J., Ratajczak, M. Z., & Lane, A. N. (2008) · Molecular Cancer · doi:10.1186/1476-4598-7-79 · Cited by 67
Self-citation(2012) · Methods in pharmacology and toxicology · doi:10.1007/978-1-61779-618-0 · Cited by 60
Lorkiewicz, P. K., Higashi, R. M., Lane, A. N., & Fan, T. W. ‐. (2011) · Metabolomics · doi:10.1007/s11306-011-0388-y · Cited by 58
Self-citationFan, T. W. ‐., Yuan, P., Lane, A. N., Higashi, R. M., Wang, Y., Hamidi, A., Zhou, R., Guitart, X., Chen, G., Manji, H. K., et al. (2010) · Metabolomics · doi:10.1007/s11306-010-0208-9 · Cited by 57
Self-citationTumor M2-PK and glutaminolytic enzymes in the metabolic shift of tumor cells.
Mazurek, S., Grimm, H., Oehmke, M. J., Weisse, G., Teigelkamp, S., & EIGENBRODT, E. (2000) · PubMed · Cited by 55
Stable isotope‐assisted metabolomics in cancer research
Lane, A. N., Fan, T. W. ‐., & Higashi, R. M. (2008) · IUBMB Life · doi:10.1002/iub.17 · Cited by 45
Self-citationConsiderations of Sample Preparation for Metabolomics Investigation
Fan, T. W. ‐. (2012) · Methods in pharmacology and toxicology · doi:10.1007/978-1-61779-618-0_2 · Cited by 35
Self-citationRegulation of the breakdown rates of biotin-containing proteins in Swiss 3T3-L1 cells
Chandler, C. S., & Ballard, F. J. (1988) · Biochemical Journal · doi:10.1042/bj2510749 · Cited by 28
Metabolic profiling identifies lung tumor responsiveness to erlotinib
Fan, T. W. ‐., Lane, A. N., Higashi, R. M., Bousamra, M., Kloecker, G. H., & Miller, D. M. (2009) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2009.04.004 · Cited by 27
Self-citationAnaplerosis in cancer: Another step beyond the warburg effect
Ochoa-Ruiz, E., & Díaz-Ruiz, R. (2012) · American Journal of Molecular Biology · doi:10.4236/ajmb.2012.24031 · Cited by 17
Metabolomics-Edited Transcriptomics Analysis (META)
Fan, T. W. ‐. (2012) · Methods in pharmacology and toxicology · doi:10.1007/978-1-61779-618-0_14 · Cited by 13
Self-citationMetabolomics-Edited Transcriptomics Analysis (Meta)
Fan, T. W. ‐. (2010) · Elsevier eBooks · doi:10.1016/b978-0-08-046884-6.00239-6 · Cited by 8
Self-citationClinical Aspects of Metabolomics
Bousamra, M., Day, J., Fan, T. W. ‐., Kloecker, G. H., Lane, A. N., & Miller, D. M. (2012) · Methods in pharmacology and toxicology · doi:10.1007/978-1-61779-618-0_3 · Cited by 3
Self-citation
Flagged first, then by citations
Research works printed but not linked: 6
- Serkova, 2007, Curr Opin Mol Ther., 9, 572
- Mazurek, 2000, Anticancer Res., 20, 5151
- Warburg, 1923, Biochem Zeitschr., 142, 317
- Mazurek, 2003, Anticancer Res., 23, 1149
- Lobo, 2000, Biochem J., 348, 257, 10.1042/0264-6021:3480257 · DOI · Paper page
- 10.1016/j.cmet.2012.05.001 · DOI · Paper page
Cited by
Sorted by citations
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
Metabolomics: beyond biomarkers and towards mechanisms
Johnson, C. H., Ivanisevic, J., & Siuzdak, G. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.25 · Cited by 2,829
Understanding the Intersections between Metabolism and Cancer Biology
Heiden, M. G. V., & DeBerardinis, R. J. (2017) · Cell · doi:10.1016/j.cell.2016.12.039 · Cited by 2,369
From Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119
Metadata
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
