Cells Lacking the Fumarase Tumor Suppressor Are Protected from Apoptosis through a Hypoxia-Inducible Factor-Independent, AMPK-Dependent Mechanism
Open accessAbstract
Loss-of-function mutations of the tumor suppressor gene encoding fumarase (FH) occur in individuals with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). We found that loss of FH activity conferred protection from apoptosis in normal human renal cells and fibroblasts. In FH-defective cells, both hypoxia-inducible factor 1α (HIF-1α) and HIF-2α accumulated, but they were not required for apoptosis protection. Conversely, AMP-activated protein kinase (AMPK) was activated and required, as evidenced by the finding that FH inactivation failed to protect AMPK-null mouse embryo fibroblasts (MEFs) and AMPK-depleted human renal cells. Activated AMPK was detected in renal cysts, which occur in mice with kidney-targeted deletion of Fh1 and in kidney cancers of HLRCC patients. In Fh1-null MEFs, AMPK activation was sustained by fumarate accumulation and not by defective energy metabolism. Addition of fumarate and succinate to kidney cells led to extracellular signal-regulated kinase 1/2 (ERK1/2) and AMPK activation, probably through a receptor-mediated mechanism. These findings reveal a new mechanism of tumorigenesis due to FH loss and an unexpected pro-oncogenic role for AMPK that is important in considering AMPK reactivation as a therapeutic strategy against cancer.
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
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?
Loss of fumarate hydratase causes HIF-independent activation of AMPK via a receptor-mediated mechanism rather than metabolic activity of accumulated fumarate.
“Another mode of HIF-independent activation of AMPK was attributed to the loss of fumarate hydratase, where a receptor-mediated mechanism rather than metabolic activity of accumulated fumarate was a casual factor [186].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [186]
In “Fumarase knockdown protects cells from apoptosis by activating AMPK” (page not provided), the paper links FH loss to AMPK activation through fumarate accumulation rather than energetic impairment or altered metabolic signaling. It says the activation kinetics suggest a receptor-mediated mechanism, but does not establish that mechanism as the causal factor. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380 · see citing works
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.022 · Cited by 2,108 · cited 2× · see citing works
“In agreement with previous reports (42, 51), we found that FH loss in normal kidney cells leads to both HIF-1 and HIF-2 accumulation but that these factors are not required for protection from apoptosis in this context.”
BackgroundResultShaw, R. J., Kosmatka, M., Bardeesy, N., Hurley, R. L., Witters, L. A., DePinho, R. A., & Cantley, L. C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308061100 · Cited by 1,797 · see citing works
Isaacs, J. S., Jung, Y. J., Mole, D. R., Lee, S., Torres-Cabala, C., Chung, Y.-L., Merino, M., Trepel, J., Zbar, B., Toro, J., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.017 · Cited by 958 · see citing works
Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors
He, W., Miao, F. J.-P., Lin, D. C.-H., Schwandner, R. T., Wang, Z., Gao, J., Chen, J.-L., Tian, H., & Ling, L. (2004) · Nature · doi:10.1038/nature02488 · Cited by 909 · cited 5× · see citing works
“Another potential mechanism linking fumarate with AMPK activation is the involvement of G-protein-coupled receptors (GPCRs) (22).”
BackgroundInfluentialJiralerspong, S., Palla, S. L., Giordano, S. H., Meric-Bernstam, F., Liedtke, C., Barnett, C. M., Hsu, L., Hung, M.-C., Hortobagyi, G. N., & Gonzalez-Angulo, A. M. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.19.6410 · Cited by 880 · cited 1× · see citing works
“Preclinical (20, 21) and epidemiological (24, 31, 32) studies have prompted clinical trials (12, 15) to evaluate the effects of metformin on the treatment or prevention of human cancer.”
BackgroundRussell, R. R., Li, J., Coven, D. L., Pypaert, M., Zechner, C., Palmeri, M., Giordano, F. J., Mu, J., Birnbaum, M. J., & Young, L. H. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19297 · Cited by 738 · see citing works
Metabolic signatures of exercise in human plasma
Lewis, G. D., Farrell, L., Wood, M. J., Martinovic, M., Arany, Z., Rowe, G. C., Souza, A., Cheng, S., McCabe, E. L., Yang, E., et al. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3001006 · Cited by 432 · see citing works
MacKenzie, E. D., Selak, M. A., Tennant, D. A., Payne, L. J., Crosby, S., Frederiksen, C. M., Watson, D. G., & Gottlieb, E. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01927-06 · Cited by 359 · see citing works
Sudarshan, S., Sourbier, C., Kong, H.-S., Block, K., Romero, V. A. V., Yang, Y., Galindo, C., Mollapour, M., Scroggins, B., Goode, N., et al. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00483-09 · Cited by 217 · see citing works
Tong, W.-H., Sourbier, C., Kovtunovych, G., Jeong, S. Y., Vira, M., Ghosh, M., Romero, V. V., Sougrat, R., Vaulont, S., Viollet, B., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.07.018 · Cited by 212 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Mankouri J, et al. 2010. Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase. Proc. Natl. Acad. Sci. U. S. A. 107:11549 -11554.
Cited by
Sorted by citations
Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis
Tian, R., Abarientos, A., Hong, J., Hashemi, S. H., Yan, R., Dräger, N., Leng, K., Nalls, M. A., Singleton, A. B., Xu, K., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00862-0 · Cited by 414 · see citing works
HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells
Lee, S.-H., Golinska, M., & Griffiths, J. R. (2021) · Cells · doi:10.3390/cells10092371 · Cited by 169 · see citing works
Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions
Guitart, A. V., Panagopoulou, T. I., Villacreces, A., Vukovic, M., Sepulveda, C., Allen, L., Carter, R. N., van de Lagemaat, L. N., Morgan, M., Giles, P., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20161087 · Cited by 86 · see citing works
Self-citationGenome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis
Tian, R., Abarientos, A., Hong, J., Hashemi, S. H., Yan, R., Dräger, N., Leng, K., Nalls, M. A., Singleton, A. B., Xu, K., et al. (2020) · doi:10.1101/2020.06.27.175679 · Cited by 414 · see citing works
- Authors
- Bardella, C., Olivero, M., Lorenzato, A., Geuna, M., Adam, J., O'Flaherty, L., Rustin, P., Tomlinson, I., Pollard, P. J., & Di Renzo, M. F.
- Affiliations
- Candiolo Cancer Institute (IT)
- A. O. Ordine Mauriziano di Torino (IT)
- University of Oxford (GB)
- Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, United Kingdom
- Inserm (FR)
- Centre for Human Genetics (GB)
- Department of Oncological Sciences, University of Torino, School of Medicine, Turin, Italy
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2012-08-01
- Volume
- 32
- Issue
- 15
- Pages
- 3081-3094
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3434507
- OpenAlex
- W2133933613
- Cited by
- 33
- References
- 11
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 10 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 5
- FWCI
- 1.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wake Forest University
- Wellcome Trust (WT091112MA, 090532)
- Institut National de la Santé et de la Recherche Médicale (U1016)
- Centre National de la Recherche Scientifique
- Associazione Italiana per la Ricerca sul Cancro
- Université Paris Descartes
- Regione Piemonte
- Wake Forest School of Medicine
- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Keywords
- fumarase, apoptosis resistance, AMPK, hypoxia-inducible factor, HIF-1α, HIF-2α, fumarate accumulation, succinic acid, ERK1/2, renal cysts, hereditary leiomyomatosis and renal cell cancer syndrome, kidney cancer, tumor suppressor loss
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Cell Line, Fumarate Hydratase, Fumarates, Humans, Kidney Neoplasms, Neoplastic Syndromes, Hereditary, Skin Neoplasms, Uterine Neoplasms, Signal Transduction, Apoptosis, Reactive Oxygen Species, Leiomyomatosis, Mitogen-Activated Protein Kinase 1, Tumor Suppressor Proteins, RNA Interference, RNA, Small Interfering, Mitogen-Activated Protein Kinase 3, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, AMP-Activated Protein Kinases
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
