The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Therapeutic Targeting of the Warburg Effect in Pancreatic Cancer Relies on an Absence of p53 Function
Open accessPublished version of a preprint
Abstract
The “Warburg effect” describes a peculiar metabolic feature of many solid tumors, namely their increased glucose uptake and high glycolytic rates, which allow cancer cells to accumulate building blocks for the biosynthesis of macromolecules. During aerobic glycolysis, pyruvate is preferentially metabolized to lactate by the enzyme lactate dehydrogenase-A (LDH-A), suggesting a possible vulnerability at this target for small-molecule inhibition in cancer cells. In this study, we used FX11, a small-molecule inhibitor of LDH-A, to investigate this possible vulnerability in a panel of 15 patient-derived mouse xenograft (PDX) models of pancreatic cancer. Unexpectedly, the p53 status of the PDX tumor determined the response to FX11. Tumors harboring wild-type (WT) TP53 were resistant to FX11. In contrast, tumors harboring mutant TP53 exhibited increased apoptosis, reduced proliferation indices, and attenuated tumor growth when exposed to FX11. [18F]-FDG PET-CT scans revealed a relative increase in glucose uptake in mutant TP53 versus WT TP53 tumors, with FX11 administration downregulating metabolic activity only in mutant TP53 tumors. Through a noninvasive quantitative assessment of lactate production, as determined by 13C magnetic resonance spectroscopy (MRS) of hyperpolarized pyruvate, we confirmed that FX11 administration inhibited pyruvate-to-lactate conversion only in mutant TP53 tumors, a feature associated with reduced expression of the TP53 target gene TIGAR, which is known to regulate glycolysis. Taken together, our findings highlight p53 status in pancreatic cancer as a biomarker to predict sensitivity to LDH-A inhibition, with regard to both real-time noninvasive imaging by 13C MRS as well as therapeutic response. Cancer Res; 75(16); 3355–64. ©2015 AACR.
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
“altered p53 function has a multitude of tumor-promoting effects on neoplastic cells, including increased genomic instability30, reprogrammed cellular metabolism57,58, and enhanced metastatic propensity59.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [58]
In the citing paper
“Directly targeting glycolysis through lactate dehydrogenase inhibition has shown mixed results depending on p53 status58”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [58]
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
Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M., & Matrisian, L. M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0155 · Cited by 7,094
Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses
Jones, S., Zhang, X., Parsons, D. W., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Kamiyama, H., Jimeno, A., et al. (2008) · Science · doi:10.1126/science.1164368 · Cited by 3,969
Self-citationTumor cell metabolism: cancer's Achilles' heel
Kroemer, G., & Pouyssegur, J. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.05.005 · Cited by 2,337
TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis
Bensaad, K., Tsuruta, A., Selak, M. A., Vidal, M. N. C., Nakano, K., Bartrons, R., Gottlieb, E., & Vousden, K. H. (2006) · Cell · doi:10.1016/j.cell.2006.05.036 · Cited by 2,019
Inhibitory effect of tumor cell-derived lactic acid on human T cells
Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., et al. (2007) · Blood · doi:10.1182/blood-2006-07-035972 · Cited by 1,946
Hypoxia signalling in cancer and approaches to enforce tumour regression
Pouysségur, J., Dayan, F., & Mazure, N. M. (2006) · Nature · doi:10.1038/nature04871 · Cited by 1,676
Fantin, V. R., St-Pierre, J., & Leder, P. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.04.023 · Cited by 1,635
Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression
Le, A., Cooper, C. R., Gouw, A. M., Dinavahi, R., Maitra, A., Deck, L. M., Royer, R. E., Jagt, D. L. V., Semenza, G. L., & Dang, C. V. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914433107 · Cited by 1,528
Self-citationThe Role of Autophagy in Cancer: Therapeutic Implications
Yang, Z. J., Chee, C. E., Huang, S., & Sinicrope, F. A. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0047 · Cited by 1,243
Cited by
Sorted by citations
Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321
Self-citationTargeting cancer metabolism in the era of precision oncology
Stine, Z. E., Schug, Z. T., Salvino, J. M., & Dang, C. V. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00339-6 · Cited by 1,189
Self-citationGenetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527
Hyperpolarized 13C MRI: Path to Clinical Translation in Oncology
Kurhanewicz, J. V., Vigneron, D. B., Ardenkjær‐Larsen, J. H., Bankson, J. A., Brindle, K. M., Cunningham, C. H., Gallagher, F. A., Keshari, K. R., Kjær, A., Laustsen, C., et al. (2018) · Neoplasia · doi:10.1016/j.neo.2018.09.006 · Cited by 441
Metabolism of pancreatic cancer: paving the way to better anticancer strategies
Qin, C., Yang, G., Yang, J., Ren, B., Wang, H., Chen, G., Zhao, F., You, L., Wang, W., & Zhao, Y. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01169-7 · Cited by 433
Metadata
- Authors
- Rajeshkumar, N. V., Dutta, P., Yabuuchi, S., de Wilde, R. F., Martinez, G. V., Le, A., Kamphorst, J. J., Rabinowitz, J. D., Jain, S. K., Hidalgo, M., Dang, C. V., Gillies, R. J., & Maitra, A.
- Affiliations
- Johns Hopkins University (US)
- Moffitt Cancer Center (US)
- 1Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
- Princeton University (US)
- Spanish National Cancer Research Centre (ES)
- Abramson Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Maitra, Anirban
- ORCID
- Venue
- Cancer Research
- Published
- 2015-08-13
- Volume
- 75
- Issue
- 16
- Pages
- 3355-3364
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4537812
- OpenAlex
- W2164355096
- Cited by
- 158
- References
- 48
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 12 · 2023: 12 · 2022: 14 · 2021: 29 · 2020: 16 · 2019: 14 · 2018: 15 · 2017: 12 · 2016: 15 · 2015: 4
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research UK (22311)
- National Cancer Institute (R01CA113669, R01CA057341, R01CA077575, R01CA051497, R01CA163591, P30CA016520)
- 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 › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- Warburg effect, pancreatic cancer, p53 status, TP53 mutation, aerobic glycolysis, lactic acid production, TIGAR, glucose metabolism, patient-derived xenografts, predictive biomarkers, 13C NMR, hyperpolarized pyruvate, 18F-FDG PET/CT
- MeSH terms
- Lactate Dehydrogenase 5, Animals, Glycolysis, Humans, Immunohistochemistry, Isoenzymes, L-Lactate Dehydrogenase, Lactates, Male, Mice, Nude, Mutation, Naphthalenes, Pancreatic Neoplasms, Phosphoric Monoester Hydrolases, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Apoptosis, Pyruvic Acid, Fluorodeoxyglucose F18, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays, Tumor Burden, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Positron-Emission Tomography, Apoptosis Regulatory Proteins, Carbon-13 Magnetic Resonance Spectroscopy
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
