Tumour-associated mutant p53 drives the Warburg effect
Open accessAbstract
Tumour cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Its mechanism is not well understood. The tumour suppressor gene p53 is frequently mutated in tumours. Many tumour-associated mutant p53 (mutp53) proteins not only lose tumour suppressive function but also gain new oncogenic functions that are independent of wild-type p53, defined as mutp53 gain of function (GOF). Here we show that tumour-associated mutp53 stimulates the Warburg effect in cultured cells and mutp53 knockin mice as a new mutp53 GOF. Mutp53 stimulates the Warburg effect through promoting GLUT1 translocation to the plasma membrane, which is mediated by activated RhoA and its downstream effector ROCK. Inhibition of RhoA/ROCK/GLUT1 signalling largely abolishes mutp53 GOF in stimulating the Warburg effect. Furthermore, inhibition of glycolysis in tumour cells greatly compromises mutp53 GOF in promoting tumorigenesis. Thus, our results reveal a new mutp53 GOF and a mechanism for controlling the Warburg effect.
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GOF mut-p53 induces an anomalous, carcinogenic metabolism (i.e., lipid metabolism and Warburg effect) and disturbed tissue architecture.
“In addition, GOF mut-p53 induces an anomalous, carcinogenic metabolism (i.e., lipid metabolism and Warburg effect) and disturbed tissue architecture [70,71].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [71]
The Abstract and Results report that gain-of-function mutant p53 stimulates the Warburg effect and that this contributes to tumorigenesis. The Discussion mentions lipid metabolism as a function reported by earlier studies, but our copy does not support the claim that mutant p53 disturbs tissue architecture. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPancreatic cancers generate substantial lactic acid fluxes, linked to mutations that promote hyper-proliferation.
“pancreatic cancers generate substantial lactic acid fluxes, linked to mutations that promote hyper-proliferation”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [18]
The Results section ('Mutp53 stimulates the Warburg Effect in vitro and in vivo'; page unavailable) reports increased lactate production in mutant-p53 lung and breast cancer cells and links mutant p53 to the Warburg effect. It does not establish substantial lactic acid fluxes in pancreatic cancers specifically, or show that those fluxes are linked to mutations promoting hyper-proliferation there. The only pancreatic-cancer mention found is in a reference title. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTP53 mutations disinhibit glucose metabolism.
“mutations in TP53 disinhibit glucose metabolism.18,19”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [18]
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References 65 · Cited by 434
- Authors
- Zhang, C., Liu, J., Liang, Y., Wu, R., Zhao, Y., Hong, X., Lin, M., Yu, H., Liu, L., Levine, A. J., Hu, W., & Feng, Z.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Harbin Medical University (CN)
- Institute for Advanced Study (US)
- Corresponding author
- Hu, Wenwei
- Feng, Zhaohui
- ORCID
- Venue
- Nature Communications
- Published
- 2013-12-17
- Volume
- 4
- Issue
- 1
- Pages
- 2935-2935
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3969270
- OpenAlex
- W2067265392
- Cited by
- 434
- References
- 65
- Citations by year
- 2026: 19 · 2025: 35 · 2024: 37 · 2023: 46 · 2022: 38 · 2021: 48 · 2020: 51 · 2019: 30 · 2018: 32 · 2017: 25 · 2016: 32 · 2015: 26 · 2014: 12 · 2013: 2
- FWCI
- 8.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Defense (W81XWH)
- Ellison Medical Foundation
- National Institutes of Health (W81XWH)
- National Cancer Institute (R01CA143204, P01CA087497, R01CA160558, P30CA072720)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mutant p53, Warburg effect, aerobic glycolysis, RhoA, rocks, gain-of-function, tumor suppressor, glucose uptake, carcinogenesis, glycolysis inhibition
- MeSH terms
- Actins, Animals, Cell Membrane, Cells, Cultured, Glucose, Humans, Lactates, Male, Mice, Inbred BALB C, Mice, Transgenic, Mutation, Neoplasms, Genes, p53, Tumor Suppressor Protein p53, rhoA GTP-Binding Protein, Xenograft Model Antitumor Assays, Cell Line, Tumor, Glucose Transporter Type 1, Mice, rho-Associated Kinases, Walker-Warburg Syndrome
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