HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability
Open accessAbstract
Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.
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The HIF hydroxylases have been reported to be inhibited by citrate, isocitrate, succinate, fumarate, malate, oxaloacetate, and pyruvate.
“In addition to requiring 2-oxoglutarate as a cosubstrate, the HIF hydroxylases have been reported to be inhibited by citrate, isocitrate, succinate, fumarate, malate, oxaloacetate, and pyruvate (Dalgard et al., 2004; Hewitson et al., 2007; Isaacs et al., 2005; Koivunen et al., 2007a; Selak et al., 2005).”
From Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. (2008) · cites this paper as Isaacs et al., 2005
The clearest evidence that metabolites modulate HIF signaling comes from cells that are genetically defective in fumarate hydratase or succinate dehydrogenase.
“To date, the clearest evidence that metabolites modulate HIF signaling comes from cells that are genetically defective in fumarate hydratase (FH) (Isaacs et al., 2005) or succinate hydrogenase (SDH; subunits b, c, and d) (MacKenzie et al., 2007; Pollard et al., 2005; Selak et al., 2005).”
From Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. (2008) · cites this paper as Isaacs et al., 2005
Fumarate contributes to inactivation of PHD, stabilizing HIF proteins to promote cell survival.
“Similar to succinate, fumarate contributes to the inactivation of PHD, stabilizing HIF proteins to promote cell survival133”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [133]
HIF1α accumulates in SDH and FH mutant tumors, presumably due to inhibition of EglN prolyl hydroxylases.
“For example, the HIF1α transcription factor accumulates in SDH and FH mutant tumors, presumably due to inhibition of the EglN prolyl hydroxylases (Dahia et al., 2005; Isaacs et al., 2005; Pollard et al., 2005, 2007; Selak et al., 2005).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Isaacs et al., 2005
Loss of fumarate hydratase activity leads to accumulation of fumarate, which can inhibit PHD competitively.
“A similar model of substrate-mediated PHD inhibition has been described (23, 37, 42) in which the loss of fumarate hydratase activity leads to the accumulation of fumarate, which also can inhibit PHD competitively.”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [23]
PHDs are inactive at low O2 and can be inactivated by accumulation of TCA metabolites fumarate and succinate.
“PHDs are inactive at low O2 and can be inactivated by the accumulation of TCA metabolites fumarate and succinate, which may occur from mutations in the tumor suppressor genes succinate dehydrogenase subunit B or fumarate hydratase (187, 334, 384).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [187]
Succinate and fumarate accumulation can inhibit αKG-dependent prolyl hydroxylases, leading to stabilization of HIF-1 and activation of the HIF/hypoxia transcriptional program.
“In addition to affecting the activity of chromatin-associated αKG-dependent dioxygenases, succinate and fumarate accumulation can also inhibit αKG-dependent prolyl hydroxylases, leading to stabilization of HIF-1 and concomitant activation of the HIF/hypoxia transcriptional program (184, 185).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [184]
High levels of succinate and fumarate can inhibit PHD2 activity through product-mediated inhibition of PHD function, leading to HIF-1α protein stabilization under normoxic (20% O2) conditions.
“High levels of succinate and fumarate can inhibit PHD2 activity through product-mediated inhibition of PHD function, leading to HIF-1α protein stabilization under normoxic (20% O2) conditions (100, 101).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [100]
Fumarate can inhibit PHD2.
“Subsequent work confirmed that fumarate could inhibit PHD2 (Isaacs et al., 2005)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Isaacs et al., 2005
Elevated levels of succinate or fumarate can inhibit PHD activity.
“elevated levels of succinate or fumarate can inhibit PHD activity [65, 66]”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [65]
Both succinate and fumarate are competitive PHD inhibitors, and massive accumulation of these metabolites in cells lacking SDH or FH activity elicits a hypoxic response even under oxygen-replete conditions.
“Both succinate and fumarate are competitive PHD inhibitors, and the massive accumulation of these metabolites in cells lacking SDH or FH activity elicit a hypoxic response even under oxygen-replete condition (Isaacs et al., 2005; Selak et al., 2005).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Isaacs et al., 2005
Both succinate and fumarate aberrantly increase the function of hypoxia inducible factors (HIFs).
“Furthermore, both succinate and fumarate aberrantly increase the function of hypoxia inducible factors (HIFs).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Isaacs et al., 2005
In D2HGA, about 50% of patients present with D2HGDH mutations, while the remaining half possess mutations in IDH2.
“In the case of D2HGA, about 50% of patients present with D2HGDH mutations, while the remaining half possess mutations in the Krebs cycle enzyme isocitrate dehydrogenase 2 (IDH2), which converts isocitrate to α-KG110.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [110]
Cites
Warburg, O. (1956) · Science · doi:10.1126/science.123.3191.309 · Cited by 13,425 · see citing works
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717 · see citing works
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
Self-citationThe tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180 · see citing works
Self-citationIvan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · see citing works
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333 · see citing works
Self-citationA conserved family of prolyl-4-hydroxylases that modify HIF
Bruick, R. K., & McKnight, S. L. (2001) · Science · doi:10.1126/science.1066373 · Cited by 2,549 · see citing works
Cellular and developmental control of O <sub>2</sub> homeostasis by hypoxia-inducible factor 1α
Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., et al. (1998) · Genes & Development · doi:10.1101/gad.12.2.149 · Cited by 2,476 · see citing works
(1999) · PubMed · Cited by 2,204 · 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 3× · see citing works
“Succinate also upregulates HIF by inhibiting its proline hydroxylation (Selak et al., 2005), but in vitro enzyme kinetic analysis proves it to be a weaker antagonist of 2-OG, a finding in keeping with its reduced potency (relative to fumarate) in causing intracellular HIF accumulation in A549 cells.”
BackgroundInfluentialSemenza, G. L., Jiang, B.-H., Leung, S. W., Passantino, R., Concordet, J.-P., Maire, P., & Giallongo, A. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.51.32529 · Cited by 1,752 · see citing works
Mutations of the VHL tumour suppressor gene in renal carcinoma
Gnarra, J. R., Tory, K., Weng, Y., Schmidt, L., Wei, M. H., Li, H., Latif, F., Liu, S., Chen, F., Duh, F.-M., et al. (1994) · Nature Genetics · doi:10.1038/ng0594-85 · Cited by 1,730 · see citing works
Self-citationMutations in <i>SDHD</i> , a Mitochondrial Complex II Gene, in Hereditary Paraganglioma
Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., Mey, A. V. D., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., et al. (2000) · Science · doi:10.1126/science.287.5454.848 · Cited by 1,638 · see citing works
The Multiple Leiomyoma Consortium (2002) · Nature Genetics · doi:10.1038/ng849 · Cited by 1,635 · see citing works
HIF‐1α is required for solid tumor formation and embryonic vascularization
Ryan, H. E., Lo, J., & Johnson, R. S. (1998) · The EMBO Journal · doi:10.1093/emboj/17.11.3005 · Cited by 1,579 · see citing works
Ohh, M., Park, C. W., Ivan, M., Hoffman, M. A., Kim, T.-Y., Huang, L. E., Pavletich, N., Chau, V., & Kaelin, W. G. (2000) · Nature Cell Biology · doi:10.1038/35017054 · Cited by 1,577 · see citing works
Berra, E., Benizri, E., Ginouvès, A., Volmat, V., Roux, D., & Pouysségur, J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg392 · Cited by 1,348 · see citing works
Talks, K. L., Turley, H., Gatter, K. C., Maxwell, P. H., Pugh, C. W., Ratcliffe, P. J., & Harris, A. L. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64554-3 · Cited by 1,312 · see citing works
Self-citationDimerization, DNA Binding, and Transactivation Properties of Hypoxia-inducible Factor 1
Jiang, B.-H., Rue, E., Wang, G. L., Roe, R., & Semenza, G. L. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.30.17771 · Cited by 1,106 · see citing works
Astuti, D., Latif, F., Dallol, A., Dahia, P. L. M., Douglas, F., George, E., Sköldberg, F., Husebye, E. S., Eng, C., & Maher, E. R. (2001) · The American Journal of Human Genetics · doi:10.1086/321282 · Cited by 1,087 · see citing works
Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein.
Iliopoulos, O., Levy, A. P., Jiang, C., Kaelin, W. G., & Goldberg, M. A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.20.10595 · Cited by 882 · see citing works
Mutations in SDHC cause autosomal dominant paraganglioma, type 3
Niemann, S., & Müller, U. (2000) · Nature Genetics · doi:10.1038/81551 · Cited by 875 · see citing works
HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation
Yu, F., White, S. B., Zhao, Q., & Lee, F. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181341498 · Cited by 796 · see citing works
Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein
Kondo, K., Klco, J., Nakamura, E., Lechpammer, M., & Kaelin, W. G. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00043-0 · Cited by 761 · see citing works
Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL
Hon, W.-C., Wilson, M. I., Harlos, K., Claridge, T. D. W., Schofield, C. J., Pugh, C. W., Maxwell, P. H., Ratcliffe, P. J., Stuart, D. I., & Jones, E. Y. (2002) · Nature · doi:10.1038/nature00767 · Cited by 751 · cited 1× · see citing works
“Indeed, the presence of a hydroxyproline binding pocket in the VHL protein (Hon et al., 2002) suggests that other”
BackgroundSelf-citationTumour suppression by the human von Hippel-Lindau gene product
Iliopoulos, O., Kibel, A. S., Gray, S. G., & Kaelin, W. G. (1995) · Nature Medicine · doi:10.1038/nm0895-822 · Cited by 696 · see citing works
Inherited susceptibility to uterine leiomyomas and renal cell cancer
Launonen, V., Vierimaa, O., Kiuru, M., Isola, J., Roth, S., Pukkala, E., Sistonen, P., Herva, R., & Aaltonen, L. A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051633798 · Cited by 669 · see citing works
Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway
Isaacs, J. S., Jung, Y.-J., Mimnaugh, E. G., Martinez, A., Cuttitta, F., & Neckers, L. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204733200 · Cited by 663 · see citing works
Self-citationToro, J. R., Nickerson, M. L., Wei, M.-H., Warren, M. B., Glenn, G. M., Turner, M. L. C., Stewart, L., Duray, P. H., Tourre, O., Sharma, N. D., et al. (2003) · The American Journal of Human Genetics · doi:10.1086/376435 · Cited by 633 · see citing works
Self-citation(2000) · PubMed · Cited by 614 · see citing works
Inhibition of HIF2α Is Sufficient to Suppress pVHL-Defective Tumor Growth
Kondo, K., Kim, W. Y., Lechpammer, M., & Kaelin, W. G. (2003) · PLoS Biology · doi:10.1371/journal.pbio.0000083 · Cited by 611 · see citing works
Energetic basis of brain activity: implications for neuroimaging
Shulman, R. G., Rothman, D. L., Behar, K. L., & Hyder, F. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.06.005 · Cited by 590 · see citing works
Lee, S., Nakamura, E., Yang, H., Wei, W., Linggi, M. S., Sajan, M. P., Farese, R. V., Freeman, R. S., Carter, B. D., Kaelin, W. G., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.015 · Cited by 527 · see citing works
Self-citationc-Myc is essential for vasculogenesis and angiogenesis during development and tumor progressionPreprint
Baudino, T. A., McKay, C., Pendeville, H., Nilsson, J. A., Maclean, K. H., White, E. L., Davis, A. C., Ihle, J. N., & Cleveland, J. L. (2002) · Genes & Development · doi:10.1101/gad.1024602 · Cited by 516 · see citing works
Iwai, K., Yamanaka, K., Kamura, T., Minato, N., Conaway, R. C., Conaway, J. W., Klausner, R. D., & Pause, A. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.22.12436 · Cited by 508 · see citing works
Maranchie, J. K., Vasselli, J. R., Riss, J., Bonifacino, J. S., Linehan, W. M., & Klausner, R. D. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00044-2 · Cited by 433 · see citing works
Self-citationA role for mitochondrial enzymes in inherited neoplasia and beyond
Eng, C., Kiuru, M., Fernandez, M. J., & Aaltonen, L. A. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1013 · Cited by 392 · see citing works
Vanharanta, S., Buchta, M., McWhinney, S. R., Virta, S. K., Peçzkowska, M., Morrison, C. D., Lehtonen, R., Januszewicz, A., Järvinen, H., Juhola, M., et al. (2004) · The American Journal of Human Genetics · doi:10.1086/381054 · Cited by 389 · see citing works
Minchenko, О. H., Leshchinsky, I., Opentanova, I., Sang, N., Srinivas, V., Armstead, V. E., & Caro, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110978200 · Cited by 370 · see citing works
Gimenez-Roqueplo, A.-P., Favier, J., Rustin, P., Mourad, J.-J., Plouin, P.-F., Corvol, P., Rötig, A., & Jeunemaitre, X. (2001) · The American Journal of Human Genetics · doi:10.1086/324413 · Cited by 364 · see citing works
(2003) · PubMed · Cited by 350 · see citing works
Self-citationRegulation of GLUT1 Gene Transcription by the Serine/Threonine Kinase Akt1
Barthel, A., Okino, S. T., Liao, J., Nakatani, K., Li, J., Whitlock, J. P., & Roth, R. A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.29.20281 · Cited by 328 · see citing works
Alam, N. A. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg148 · Cited by 323 · see citing works
Wei, M. H., Toure, O., Glenn, G. M., Pithukpakorn, M., Neckers, L., Stolle, C., Choyke, P., Grubb, R., Middelton, L., Turner, M. L., et al. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2005.033506 · Cited by 313 · see citing works
Self-citationWiesener, M. S., Münchenhagen, P., Berger, I., Morgan, N. V., Roigas, J., Schwiertz, A., Jürgensen, J. S., Gruber, G., Maxwell, P. H., Löning, S. A., et al. (2001) · PubMed · Cited by 308 · see citing works
Inactivation of succinate dehydrogenase by 3-nitropropionate.
Coles, C. J., Edmondson, D. E., & Singer, T. P. (1979) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)50574-3 · Cited by 307 · see citing works
Wood, S. M., Gleadle, J., Pugh, C. W., Hankinson, O., & Ratcliffe, P. J. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.25.15117 · Cited by 289 · see citing works
Self-citationObach, M., Navarro‐Sabaté, À., Caro, J., Kong, X., Duran, J., Gómez, M., Perales, J. C., Ventura, F., Rosa, J. L., & Bartrons, R. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406096200 · Cited by 274 · see citing works
Zhuang, Z., Bertheau, P., Emmert-Buck, M. R., Liotta, L. A., Gnarra, J. R., Linehan, W. M., & Lubensky, I. A. (1995) · Europe PMC (PubMed Central) · Cited by 264 · see citing works
Self-citationSomatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors.
Prowse, A. H., Webster, A. R., Richards, F. M., Richard, S., Olschwang, S., Resche, F., Affara, N. A., & Maher, E. R. (1997) · Europe PMC (PubMed Central) · Cited by 215 · see citing works
The VHL tumour-suppressor gene paradigm
Kaelin, W. G., & Maher, E. R. (1998) · Trends in Genetics · doi:10.1016/s0168-9525(98)01558-3 · Cited by 213 · see citing works
Kiuru, M. H., Launonen, V., Hietala, M., Aittomäki, K., Kuismin, O., Salovaara, R., Arola, J. T., Pukkala, ., Sistonen, P., Herva, R., et al. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)61757-9 · Cited by 206 · see citing works
Bourgeron, T., Chrétien, D., Poggi-Bach, J., Doonan, S., Rabier, D., Letouzé, P., Münnich, A., Rötig, A., Landrieu, P., & Rustin, P. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117261 · Cited by 160 · see citing works
A simple spectrophotometric assay for fumarate hydratase in crude tissue extracts
Hatch, M. D. (1978) · Analytical Biochemistry · doi:10.1016/0003-2697(78)90299-3 · Cited by 126 · see citing works
3-Carbanionic substrate analogues bind very tightly to fumarase and aspartase.
Porter, D. J. T., & Bright, H. J. (1980) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)85564-3 · Cited by 114 · see citing works
Determination and comparison of specific activity of the HIF‐prolyl hydroxylases
Tuckerman, J. R., Zhao, Y., Hewitson, K. S., Tian, Y., Pugh, C. W., Ratcliffe, P. J., & Mole, D. R. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.09.005 · Cited by 105 · see citing works
Self-citationPollard, P., Wortham, N., Barclay, E., Alam, A., Elia, G., Manek, S., Poulsom, R., & Tomlinson, I. (2005) · The Journal of Pathology · doi:10.1002/path.1686 · Cited by 100 · see citing works
Gellera, C., Uziel, G., Rimoldi, M., Zeviani, M., Laverda, A. M., Carrara, F., & DiDonato, S. (1990) · Neurology · doi:10.1212/wnl.40.3_part_1.495 · Cited by 94 · see citing works
Isaacs, J. S., Jung, Y., & Neckers, L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313342200 · Cited by 76 · see citing works
Self-citationLeu‐574 of human HIF‐1α is a molecular determinant of prolyl hydroxylation
Kageyama, Y., Koshiji, M., To, K. K. W., Tian, Y., Ratcliffe, P. J., & Huang, E. L. (2004) · The FASEB Journal · doi:10.1096/fj.03-1233fje · Cited by 69 · see citing works
Self-citationA fluorescence-based assay for 2-oxoglutarate-dependent oxygenases
McNeill, L. A., Bethge, L., Hewitson, K. S., & Schofield, C. J. (2004) · Analytical Biochemistry · doi:10.1016/j.ab.2004.09.019 · Cited by 57 · see citing works
Okajima, E., & Thorgeirsson, U. P. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2386 · Cited by 33 · see citing works
Flagged first, then by citations
1 of the 63 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088 · see citing works
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251 · see citing works
Self-citationMetabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233 · see citing works
Mitochondrial TCA cycle metabolites control physiology and disease
Martínez-Reyes, I., & Chandel, N. S. (2020) · Nature Communications · doi:10.1038/s41467-019-13668-3 · Cited by 2,813 · see citing works
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875 · see citing works
Cancer cell metabolism: warburg and beyond
Hsu, P. P., & Sabatini, D. M. (2008) · Cell · doi:10.1016/j.cell.2008.08.021 · Cited by 2,452 · see citing works
Mills, E. L., Kelly, B., Logan, A., Costa, A. S. H., Varma, M., Bryant, C. E., Tourlomousis, P., Däbritz, J. H. M., Gottlieb, E., Latorre, I., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.064 · Cited by 2,291 · see citing works
Role of Mitochondria in Ferroptosis
Gao, M., Yi, J., Zhu, J., Minikes, A. M., Monian, P., Thompson, C. B., & Jiang, X. (2019) · Molecular Cell · doi:10.1016/j.molcel.2018.10.042 · Cited by 2,120 · see citing works
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
Semenza, G. L. (2010) · Oncogene · doi:10.1038/onc.2009.441 · Cited by 1,712 · see citing works
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 · see citing works
Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?
Sabharwal, S. S., & Schumacker, P. T. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3803 · Cited by 1,643 · see citing works
HIF-1: upstream and downstream of cancer metabolism
Semenza, G. L. (2009) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2009.10.009 · Cited by 1,381 · see citing works
Fueling Immunity: Insights into Metabolism and Lymphocyte Function
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363 · see citing works
HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations
Semenza, G. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67230 · Cited by 1,335 · see citing works
Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., et al. (2012) · Genes & Development · doi:10.1101/gad.191056.112 · Cited by 1,188 · see citing works
Oxygen Sensing, Hypoxia-Inducible Factors, and Disease Pathophysiology
Semenza, G. L. (2013) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012513-104720 · Cited by 1,159 · see citing works
Tumor suppressors and cell metabolism: a recipe for cancer growth
Jones, R. G., & Thompson, C. B. (2009) · Genes & Development · doi:10.1101/gad.1756509 · Cited by 1,085 · see citing works
NRF2 and cancer: the good, the bad and the importance of context
Sporn, M. B., & Liby, K. T. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3278 · Cited by 1,067 · see citing works
The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases
Chowdhury, R., Yeoh, K. K., Tian, Y., Hillringhaus, L., Bagg, E. A., Rose, N. R., Leung, I. K. H., Li, X. S., Woon, E. C. Y., Yang, M., et al. (2011) · The EMBO Reports · doi:10.1038/embor.2011.43 · Cited by 1,035 · see citing works
Self-citationGlutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021 · see citing works
Cancer Cell Metabolism: One Hallmark, Many Faces
Cantor, J. R., & Sabatini, D. M. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0345 · Cited by 945 · see citing works
Influence of Metabolism on Epigenetics and Disease
Kaelin, W. G., & McKnight, S. L. (2013) · Cell · doi:10.1016/j.cell.2013.03.004 · Cited by 920 · see citing works
Advances in Hypoxia-Inducible Factor Biology
Choudhry, H., & Harris, A. L. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.10.005 · Cited by 873 · see citing works
Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?
DeBerardinis, R. J., & Thompson, C. B. (2012) · Cell · doi:10.1016/j.cell.2012.02.032 · Cited by 858 · see citing works
The genetic basis of kidney cancer: a metabolic disease
Linehan, W. M., Srinivasan, R., & Schmidt, L. S. (2010) · Nature Reviews Urology · doi:10.1038/nrurol.2010.47 · Cited by 743 · see citing works
Self-citationThe von Hippel–Lindau tumour suppressor protein: O2 sensing and cancer
Kaelin, W. G. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2502 · Cited by 731 · see citing works
Metabolic targets for cancer therapy
Galluzzi, L., Kepp, O., Heiden, M. G. V., & Kroemer, G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4145 · Cited by 705 · see citing works
Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer
King, A., Selak, M. A., & Gottlieb, E. (2006) · Oncogene · doi:10.1038/sj.onc.1209594 · Cited by 672 · see citing works
Prabhakar, N. R., & Semenza, G. L. (2012) · Physiological Reviews · doi:10.1152/physrev.00030.2011 · Cited by 641 · see citing works
Mitochondrial tumour suppressors: a genetic and biochemical update
Gottlieb, E., & Tomlinson, I. P. M. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1737 · Cited by 617 · see citing works
Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition
Sciacovelli, M., Gonçalves, E., Johnson, T. I., Zecchini, V. R., da Costa, A. S. H., Gaude, E., Drubbel, A. V., Theobald, S. J., Abbo, S. R., Tran, M. G. B., et al. (2016) · Nature · doi:10.1038/nature19353 · Cited by 584 · see citing works
Redox regulation of mitochondrial function
Handy, D. E., & Loscalzo, J. (2012) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4123 · Cited by 588 · see citing works
Adam, J., Hatipoglu, E., O'Flaherty, L., Ternette, N., Sahgal, N., Lockstone, H., Baban, D., Nye, E., Stamp, G. W., Wolhuter, K., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.09.006 · Cited by 585 · see citing works
Self-citationGenome dynamics of the human embryonic kidney 293 lineage in response to cell biology manipulations
Lin, Y., Boone, M., Meuris, L., Lemmens, I. H., Roy, N. V., Soete, A., Reumers, J., Moisse, M., Plaisance, S., Drmanac, R., et al. (2014) · Nature Communications · doi:10.1038/ncomms5767 · Cited by 562 · see citing works
Haem 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 · see citing works
Lee, S., Nakamura, E., Yang, H., Wei, W., Linggi, M. S., Sajan, M. P., Farese, R. V., Freeman, R. S., Carter, B. D., Kaelin, W. G., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.015 · Cited by 527 · see citing works
Self-citationRegulation and function of the mammalian tricarboxylic acid cycle
Arnold, P. K., & Finley, L. W. S. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102838 · Cited by 535 · see citing works
“In addition to affecting the activity of chromatin-associated αKG-dependent dioxygenases, succinate and fumarate accumulation can also inhibit αKG-dependent prolyl hydroxylases, leading to stabilization of HIF-1 and concomitant activation of the HIF/hypoxia transcriptional program (184, 185).”
BackgroundInhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates
Koivunen, P., Hirsilä, M., Remes, A. M., Hassinen, I. E., Kivirikko, K. I., & Myllyharju, J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610415200 · Cited by 521 · see citing works
Hypoxia-Modified Cancer Cell Metabolism
Tameemi, W. A., Dale, T. P., Al-Jumaily, R. M. K., & Forsyth, N. R. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00004 · Cited by 507 · see citing works
Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity
Dahia, P. L. M. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3648 · Cited by 545 · see citing works
Hypoxia-inducible factors: central regulators of the tumor phenotype
Gordan, J. D., & Simon, M. C. (2007) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2006.12.006 · Cited by 450 · see citing works
Bell, E. L., Emerling, B. M., Ricoult, S. J. H., & Guarente, L. (2011) · Oncogene · doi:10.1038/onc.2011.37 · Cited by 440 · see citing works
Oxygen availability and metabolic adaptations
Nakazawa, M. S., Keith, B., & Simon, M. C. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.84 · Cited by 431 · see citing works
Heterogeneity of tumor-induced gene expression changes in the human metabolic network
Hu, J., Locasale, J. W., Bielas, J. H., O'Sullivan, J., Sheahan, K., Cantley, L. C., Heiden, M. G. V., & Vitkup, D. (2013) · Nature Biotechnology · doi:10.1038/nbt.2530 · Cited by 407 · see citing works
Lum, J. J., Bui, T., Gruber, M., Gordan, J. D., DeBerardinis, R. J., Covello, K. L., Simon, M. C., & Thompson, C. B. (2007) · Genes & Development · doi:10.1101/gad.1529107 · Cited by 429 · see citing works
Guzy, R. D., Sharma, B., Bell, E., Chandel, N. S., & Schumacker, P. T. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01338-07 · Cited by 427 · see citing works
Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death
García‐Bermúdez, J., Baudrier, L., Bayraktar, E. C., Shen, Y., La, K., Guarecuco, R., Yücel, B., Fiore, D., Tavora, B., Freinkman, E., et al. (2019) · Nature · doi:10.1038/s41586-019-0945-5 · Cited by 424 · see citing works
Altered metabolite levels in cancer: implications for tumour biology and cancer therapy
Sullivan, L. B., Gui, D. Y., & Heiden, M. G. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.85 · Cited by 406 · see citing works
Oncometabolites: linking altered metabolism with cancer
Yang, M. H., Soga, T., & Pollard, P. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67228 · Cited by 424 · see citing works
Lipkowitz, S., & Weissman, A. M. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3120 · Cited by 415 · see citing works
Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer
Schödel, J., Grampp, S., Maher, E. R., Moch, H., Ratcliffe, P. J., Russo, P., & Mole, D. R. (2015) · European Urology · doi:10.1016/j.eururo.2015.08.007 · Cited by 411 · see citing works
Self-citationNagao, A., Kobayashi, M., Koyasu, S., Chow, C. C. T., & Harada, H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20020238 · Cited by 411 · see citing works
Ooi, A., Wong, J.-C., Petillo, D., Roossien, D., Perrier-Trudova, V., Whitten, D., Min, B. W. H., Tan, M.-H., Zhang, Z., Yang, X. J., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.08.024 · Cited by 401 · see citing works
Bardella, C., Pollard, P. J., & Tomlinson, I. (2011) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2011.07.003 · Cited by 395 · see citing works
Reversible Inactivation of HIF-1 Prolyl Hydroxylases Allows Cell Metabolism to Control Basal HIF-1
Lu, H., Dalgard, C. L., Mohyeldin, A., McFate, T., Tait, A. S., & Verma, A. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508718200 · Cited by 400 · see citing works
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398 · see citing works
Inhibition of 2-oxoglutarate dependent oxygenases
Rose, N. R., McDonough, M. A., King, O. N. F., Kawamura, A., & Schofield, C. J. (2011) · Chemical Society Reviews · doi:10.1039/c0cs00203h · Cited by 395 · see citing works
mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3
Dodd, K. M., Yang, J., Shen, M. H., Sampson, J. R., & Tee, A. R. (2014) · Oncogene · doi:10.1038/onc.2014.164 · Cited by 391 · see citing works
Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells
McFate, T., Mohyeldin, A., Lu, H., Thakar, J. H., Henriques, J., Halim, N. D., Wu, H., Schell, M. J., Tsang, T. M., Teahan, O., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801765200 · Cited by 383 · see citing works
Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis
Daye, D., & Wellen, K. E. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.02.002 · Cited by 375 · see citing works
The PI3K/AKT Pathway and Renal Cell Carcinoma
Guo, H., Germán, P., Bai, S., Barnes, S., Guo, W., Qi, X., Lou, H., Liang, J., Jonasch, E. W., Mills, G. B., et al. (2015) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2015.03.003 · Cited by 373 · 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
Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer
Bae, T., Hallis, S. P., & Kwak, M. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01180-8 · Cited by 387 · see citing works
Menko, F. H., Maher, E. R., Schmidt, L. S., Middelton, L. A., Aittomäki, K., Tomlinson, I. P. M., Richard, S., & Linehan, W. M. (2014) · Familial Cancer · doi:10.1007/s10689-014-9735-2 · Cited by 357 · see citing works
Self-citationRegulation of Metabolism by Hypoxia-Inducible Factor 1
Semenza, G. L. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010678 · Cited by 342 · see citing works
Signalling hypoxia by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.08.111 · Cited by 343 · see citing works
Self-citationMitochondria as therapeutic targets for cancer chemotherapy
Galluzzi, L., Larochette, N., Zamzami, N., & Kroemer, G. (2006) · Oncogene · doi:10.1038/sj.onc.1209598 · Cited by 342 · see citing works
Kaelin, W. G. (2006) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev.pathol.2.010506.092049 · Cited by 335 · see citing works
Pan, Y., Mansfield, K. D., Bertozzi, C. C., Rudenko, V., Chan, D. A., Giaccia, A. J., & Simon, M. C. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01223-06 · Cited by 332 · see citing works
Metabolomics in cancer biomarker discovery: Current trends and future perspectives
Armitage, E. G., & Barbas, C. (2013) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2013.08.041 · Cited by 330 · see citing works
Hypoxia-inducible factors in the kidney
Haase, V. H. (2006) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00071.2006 · Cited by 329 · see citing works
Finley, L. W. S. (2023) · Cell · doi:10.1016/j.cell.2023.01.038 · Cited by 331 · see citing works
The Metabolic Basis of Kidney Cancer
Linehan, W. M., Schmidt, L. S., Crooks, D. R., Wei, D., Srinivasan, R., Lang, M., & Ricketts, C. J. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1354 · Cited by 336 · see citing works
Self-citationMetabolic signatures of cancer cells and stem cells
Intlekofer, A. M., & Finley, L. W. S. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0032-0 · Cited by 322 · see citing works
<i>PHD2</i> Mutation and Congenital Erythrocytosis with Paraganglioma
Ladroue, C., Carcenac, R., Leporrier, M., Gad, S., Le Hello, C., Galateau-Salle, F., Feunteun, J., Pouysségur, J., Richard, S., & Gardie, B. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0806277 · Cited by 323 · see citing works
VHL and HIF signalling in renal cell carcinogenesis
Baldewijns, M. M. L. L., van Vlodrop, I. J. H., Vermeulen, P. B., Soetekouw, P. M. M. B., van Engeland, M., & A, A. P. D. B. (2010) · The Journal of Pathology · doi:10.1002/path.2689 · Cited by 317 · see citing works
Wei, M. H., Toure, O., Glenn, G. M., Pithukpakorn, M., Neckers, L., Stolle, C., Choyke, P., Grubb, R., Middelton, L., Turner, M. L., et al. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2005.033506 · Cited by 313 · see citing works
Self-citationThe Proto-oncometabolite Fumarate Binds Glutathione to Amplify ROS-Dependent Signaling
Sullivan, L. B., Martinez-Garcia, E., Nguyen, H., Mullen, A. R., Dufour, E., Sudarshan, S., Licht, J. D., Deberardinis, R. J., & Chandel, N. S. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.05.003 · Cited by 304 · see citing works
Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes
Laukka, T., Mariani, C. J., Ihantola, T., Cao, J. Z., Hokkanen, J., Kaelin, W. G., Godley, L. A., & Koivunen, P. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.688762 · Cited by 307 · see citing works
Role of mitochondrial dysfunction in cancer progression
Hsu, C., Tseng, L., & Lee, H. (2016) · Experimental Biology and Medicine · doi:10.1177/1535370216641787 · Cited by 306 · see citing works
Mitochondrial DNA variation and cancer
Kopinski, P. K., Singh, L. N., Zhang, S., Lott, M. T., & Wallace, D. C. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00358-w · Cited by 301 · see citing works
Oxygen sensing and hypoxia signalling pathways in animals: The implications of physiology for cancer
Ratcliffe, P. J. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.251470 · Cited by 294 · see citing works
Self-citationAiding and abetting roles of NOX oxidases in cellular transformation
Block, K. L., & Gorin, Y. C. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3339 · Cited by 301 · see citing works
The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences
Cyr, A. R., & Domann, F. E. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3492 · Cited by 294 · see citing works
Masson, N., & Ratcliffe, P. J. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-3 · Cited by 296 · see citing works
Self-citationSasaki, M., Knobbe, C. B., Itsumi, M., Elia, A. J., Harris, I. S., Chio, I. I. C., Cairns, R. A., McCracken, S., Wakeham, A., Haight, J., et al. (2012) · Genes & Development · doi:10.1101/gad.198200.112 · Cited by 296 · see citing works
Oxygen Sensors at the Crossroad of Metabolism
Aragonés, J., Fraisl, P., Baes, M. I., & Carmeliet, P. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2008.10.001 · Cited by 290 · see citing works
Citrate – new functions for an old metabolite
Iacobazzi, V., & Infantino, V. (2014) · Biological Chemistry · doi:10.1515/hsz-2013-0271 · Cited by 285 · see citing works
Bersten, D. C., Sullivan, A. E., Peet, D. J., & Whitelaw, M. L. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3621 · Cited by 267 · see citing works
Fumarate induces redox-dependent senescence by modifying glutathione metabolism
Zheng, L., Cardaci, S., Jerby, L., MacKenzie, E. D., Sciacovelli, M., Johnson, T. I., Gaude, E., King, A., Leach, J. D. G., Edrada-Ebel, R., et al. (2015) · Nature Communications · doi:10.1038/ncomms7001 · Cited by 281 · see citing works
Grubb, R. L., FRANKS, M. E., Toro, J. R., Middelton, L. A., Choyke, L. T., Fowler, S. E., Torres-Cabala, C. A., Glenn, G. M., Choyke, P. L., Merino, M. J., et al. (2007) · The Journal of Urology · doi:10.1016/j.juro.2007.01.155 · Cited by 282 · see citing works
Self-citationRevisiting the TCA cycle: signaling to tumor formation
Raimundo, N., Baysal, B. E., & Shadel, G. S. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2011.06.001 · Cited by 271 · see citing works
Signaling in Control of Cell Growth and MetabolismPreprint
Ward, P. S., & Thompson, C. B. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a006783 · Cited by 270 · see citing works
Myllyharju, J. (2008) · Annals of Medicine · doi:10.1080/07853890801986594 · Cited by 264 · see citing works
Mitochondria in cancer: Not just innocent bystanders
Frezza, C., & Gottlieb, E. (2008) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2008.11.008 · Cited by 267 · see citing works
Ogawa, M., Tomita, Y., Nakamura, Y., Lee, M.-J., Lee, S., Tomita, S., Nagaya, T., Sato, K., Yamauchi, T., Iwai, H., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.14425 · Cited by 267 · see citing works
Self-citationThe Mitochondrial Chaperone TRAP1 Promotes Neoplastic Growth by Inhibiting Succinate Dehydrogenase
Sciacovelli, M., Guzzo, G., Morello, V., Frezza, C., Zheng, L., Nannini, N., Calabrese, F., Laudiero, G., Esposito, F., Landriscina, M., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.019 · Cited by 269 · see citing works
Metabolic adaptation in hypoxia and cancer
Paredes, F., Williams, H. C., & Martín, A. S. (2021) · Cancer Letters · doi:10.1016/j.canlet.2020.12.020 · Cited by 269 · see citing works
Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing
Webb, J. D., Coleman, M. L., & Pugh, C. W. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-0147-7 · Cited by 255 · see citing works
Defects in mitochondrial metabolism and cancer
Gaude, E., & Frezza, C. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-10 · Cited by 249 · see citing works
- Authors
- 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., Ratcliffe, P. J., Linehan, W. M., & Neckers, L.
- Affiliations
- National Institutes of Health (US)
- Pusan National University (KR)
- University of Oxford (GB)
- National Cancer Institute (US)
- St George's Hospital (GB)
- Corresponding author
- Neckers, Len
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2005-08
- Volume
- 8
- Issue
- 2
- Pages
- 143-153
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2059747280
- Semantic Scholar
- 6906ef0c1fe45571640c3c7a6b3c9c2d9a979a64
- Cited by
- 958
- References
- 63
- Citations by year
- 2026: 26 · 2025: 30 · 2024: 30 · 2023: 36 · 2022: 45 · 2021: 37 · 2020: 46 · 2019: 40 · 2018: 50 · 2017: 40 · 2016: 44 · 2015: 64 · 2014: 54 · 2013: 60 · 2012: 64
- FWCI
- 14.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- fumarate hydratase, hypoxia-inducible factor, fumarate, HIF prolyl hydroxylase, competitive inhibition, clear cell renal cell carcinoma, biallelic loss, cancer susceptibility, hypoxia
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adult, Alleles, Carcinoma, Renal Cell, DNA-Binding Proteins, Female, Fumarate Hydratase, Fumarates, Humans, Ketoglutaric Acids, Kidney Neoplasms, Male, Middle Aged, Nuclear Proteins, Procollagen-Proline Dioxygenase, Syndrome, Transcription Factors, Up-Regulation, Gene Expression Regulation, Neoplastic, Leiomyomatosis, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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