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Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Open accessAbstract
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
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TL;DR
In HEK293 cells, knocking down the SDHD subunit of succinate dehydrogenase caused succinate to accumulate and inhibited HIF-α prolyl hydroxylases, stabilizing HIF-1α under normoxic conditions. This provides a mechanism linking TCA cycle dysfunction to vascular tumor phenotypes without VHL mutation.
Key findings
- SDHD-targeting siRNA reduced SDH activity and raised cellular succinate from about 121 µM in controls to about 447 µM (Di3) and 441 µM (Di4); no significant change was seen in DHE oxidation or glutathione redox state, arguing against ROS as the mediator.
- SDH inhibition induced HIF-1α protein under normoxia, produced about a 3-fold increase in HRE-luciferase reporter activity, induced VEGF mRNA to levels comparable with hypoxia or CoCl₂, and increased BNIP3; HIF-2α induction was less pronounced.
- Succinate inhibited PHD activity in vitro in a dose-dependent manner, with an IC50 reported as 0.5 mM, and the membrane-permeable succinate derivative DMS (20 mM, 48 hr) elevated HIF-1α and caused nuclear HIF-1α accumulation under normoxia.
- In SDH-inhibited cells, pVHL binding to the ODD domain was reduced, consistent with decreased ODD hydroxylation; the proposed model is that mitochondrial succinate exits to the cytosol, inhibits PHD, stabilizes HIF-1α, and drives angiogenesis, metastasis, and glycolytic gene expression.
Methods
- HEK293 cells were transfected with scrambled siRNA or SDHD-targeting siRNA (Di3 or Di4); SDH activity was measured by succinate-DCIP oxidoreductase, succinate by GC-MS with deuterated succinic acid as reference, and ROS/redox state by DHE staining and glutathione assays.
- HIF readouts included Western blot for HIF-1α, HIF-2α, and BNIP3, RT-PCR for VEGF, and an HRE-luciferase reporter; PHD activity was assayed in vitro using HA-tagged ODD and cell extracts, and pVHL binding was assessed by immunoprecipitation and far Western blot.
- The study is cell-culture based, with no patient tumor samples or in vivo tumor models described.
Limitations
- Stated in the paper: DMS uptake, conversion to succinate, and metabolism are unknown; different cell types may have different thresholds and mechanisms of HIF activation; succinate may also modulate FIH; and the ROS findings conflict with C. elegans mev-1 observations, possibly due to species or mutation differences.
- Evident from the text: conclusions rely on HEK293 cells and siRNA knockdown rather than SDH-mutant tumors, transfection efficiency was about 50% so populations were mixed, and no in vivo tumor growth or patient tumor validation was performed; elevated succinate in human SDH-mutant tumors is cited as personal communication.
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In the paper
“Since pVHL binding to the ODD domain is dependent on PHD activity (Kaelin, 2002;Safran and Kaelin, 2003)”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Elevation of succinate level following downregulation of SDH leads to PHD inhibition and HIF-1␣ stabilization in cells
What the sources say
- Not checked — no full text of the sourcecites Kaelin, 2002 source
- Supportedcites Safran and Kaelin, 2003 source
The section “Prolyl hydroxylation earmarks HIF for destruction” (p. 2) says pVHL binds HIF1α only after prolyl residues in its ODD are enzymatically hydroxylated, and identifies PHD proteins as the hydroxylases. The Figure 1 discussion (p. 3) adds that when PHD cannot hydroxylate HIF, pVHL does not recognize it. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“succinate, which accumulates as a result of SDH inhibition, inhibits HIF-␣ prolyl hydroxylases in the cytosol”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“cells incubated with 20 mM DMS for 48 hr showed elevated levels of HIF-1␣ under normoxic conditions (Figure 5B).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Elevation of succinate level following downregulation of SDH leads to PHD inhibition and HIF-1␣ stabilization in cells
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition”
- Also stated in: § Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition · plain
“there was no detectable difference in DHE oxidation in Di3 and Di4-transfected cells relative to the control (compare Figures 3C and 3D to 3A).”
- Also stated in: § Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition · plain
“no significant difference was observed in the redox state of SDH-inhibited cells as compared to the control scRNAi-transfected cells (Table 1).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Di3-transfected cells, even though the total GFP-ODD level was higher than in scRNAitransfected cells (Figures 6Aiv and 6Av), the levels of pVHLassociated fluorescence were significantly lower (Figure 6C).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Elevation of succinate level following downregulation of SDH leads to PHD inhibition and HIF-1␣ stabilization in cells
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this paper, we show that downregulation of SDH activity results in the accumulation of succinate in cells”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a clear accumulation of HIF-1␣ in the nuclei of cells treated with DMS was observed (Figure 5C)”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Elevation of succinate level following downregulation of SDH leads to PHD inhibition and HIF-1␣ stabilization in cells
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“no significant difference was observed in the redox state of SDH-inhibited cells as compared to the control scRNAi-transfected cells (Table 1).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“there was no detectable difference in DHE oxidation in Di3 and Di4-transfected cells relative to the control (compare Figures 3C and 3D to 3A).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“succinate, which accumulates as a result of SDH inhibition, inhibits HIF-␣ prolyl hydroxylases in the cytosol”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Succinate moves freely between the mitochondria and the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane.
- Rests on an assumption: Succinate is the substrate for SDH in mitochondria and a product of PHD in the cytosol.
- It may state two separate claims as one. 3
- The quote only partly states this claim. 1
- Probably not a substantial claim. 2
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The IC 50 was 5.0ف mM for succinate under these reaction conditions, a level that is attainable in SDH-inhibited cells (Table 1).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Succinate is accumulated in SDH-inhibited cells
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“leading to stabilization and activation of HIF-1␣.”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
- Rests on an assumption: Succinate moves freely between the mitochondria and the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“succinate has been shown to inhibit some ␣-ketoglutarate-dependent oxygenases, including procollagen prolyl hydroxylase and thymine-7-hydroxylase (Holme, 1975;Myllyla et al., 1977).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Actin was used as loading control.”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Experimental procedures Succinic acid quantification by GCMS Plasmids
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The PHD isozymes belong to the Fe 2ϩ and ␣-ketoglutarate-dependent family of dioxygenases that split molecular oxygen to hydroxylate their substrates and, in parallel, oxidize and decarboxylate ␣-ketoglutarate to succinate (Schofield and Zhang, 1999).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Introduction
What the sources say
- Not checked — no full text of the sourcecites Schofield and Zhang, 1999 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“the PHDs utilize ␣-ketoglutarate as a cosubstrate and require ferrous iron (Fe 2ϩ ) and ascorbate as cofactors (Kaelin, 2002;Schofield and Zhang, 1999).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Introduction
What the sources say
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
Succinate moves freely between the mitochondria and the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane.
“Succinate moves freely between the mitochondria and the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane.”
The paper relies on this without support.
Succinate is the substrate for SDH in mitochondria and a product of PHD in the cytosol.
“succinate, the substrate for SDH in mitochondria and a product of PHD in the cytosol.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In intact cells, this introduces an additional level of complexity, because the lack of enzymatically active CII will result in the accumulation of its substrate succinate due to the poor membrane permeability of this metabolite.27”
From Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation (2015) · cites this paper as [27]
Experimental — accuracy not yet measuredIn the citing paper
“Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1a”
From Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations (2005) · cites this paper as [27]
In the citing paper
“Selak et al. (27) tested a model of tumorigenesis in which raised levels of succinate caused increased HIF1a expression in vitro.”
From Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations (2005) · cites this paper as [27]
In the citing paper
“neither our data nor those of Selak et al. (27) have provided evidence for an alternative model of tumorigenesis in HLRCC or HPGL based on increased levels of ROSs.”
From Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations (2005) · cites this paper as [27]
In the citing paper
“Selak et al. (27) showed that the mechanism for these findings may be inhibition by succinate of HIF PHDs, which rely for their activity on conversion of a-ketoglutarate to succinate.”
From Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations (2005) · cites this paper as [27]
In the citing paper
“Additionally, succinate and fumarate inhibit the prolyl hydroxylase domain-containing (PHD) enzymes that regulate stability of hypoxia-inducible factors (HIFs), such that FH and SDH deficient cancers activate the hypoxic gene expression program even under normoxic conditions (Hewitson et al., 2007; Pollard et al., 2005; Selak et al., 2005).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Selak et al., 2005
In the citing paper
“Metabolite accumulation in the setting of dysfunctional mitochondria can inhibit VHL-dependent degradation of hypoxia-inducible factor-α (HIF-α) subunits, creating a pseudohypoxic state that mimics VHL loss (14).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [14]
In the citing paper
“The other mechanism by which succinate supports tumorigenesis acts through the inhibition of hypoxia-inducible factor prolyl hydroxylase (PHD). PHD activates the pseudohypoxic response by stabilizing HIF-1α, which is a well-known tumorigenesis enhancer”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [127]
In the citing paper
“TCA cycle dysfunction leads to oncogenesis by regulating signaling pathway and stabilizing HIF1-α (Selak et al., 2005).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Selak et al., 2005
In the citing paper
“Dysregulated SDH activity in the setting of these mutations promotes the accumulation of succinate and mitochondrial reactive oxygen species, activating HIF1α and inducing angiogenesis (Selak et al., 2005).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Selak et al., 2005
In the citing paper
“H2O2 also can participate in the one-electron reaction with transition metal ions (e.g., Fe2+ bound to organic molecules) to generate various intermediate ferryl species (274, 275), such as Fe(IV) = O•, a powerful oxidizing agent that can lead to lipid oxidation and DNA damage, as discussed in section VI.”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [275]
In the citing paper
“High levels of succinate resulting from loss of complex II function can in turn block HIF1α degradation through inhibition of prolyl hydroxylases.”
From A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas (2005) · cites this paper as [19]
In the citing paper
“Selak et al. showed that disruption of the mitochondrial complex II results in increased HIF1α activity and that this upregulation is channeled through inhibition of prolyl hydroxylase function [19].”
From A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas (2005) · cites this paper as [19]
In the citing paper
“Succinate activates HIF-1α in tumours10,26, indicating an important similarity between inflammation and cancer.”
From Succinate is an inflammatory signal that induces IL-1β through HIF-1α (2013) · cites this paper as [10]
In the citing paper
“Succinate can be transported from the mitochondria via the dicarboxylic acid transporter to the cytosol where in excess it impairs PHD activity (by product inhibition) leading to HIF-1α stabilization and activation.”
From Succinate is an inflammatory signal that induces IL-1β through HIF-1α (2013) · cites this paper as [10]
In the citing paper
“Selak et al. reported that complex II deficiency achieved by the suppression of SdhD induces normoxic HIF-1 𝛂 stabilization via the accumulation of succinate without inducing a detectable increase in ROS production (43, 44).”
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 [43]
In the citing paper
“Decreases in Sdh activity should cause an accumulation of succinate, which can transit to the cytosol through the dicarboxylate carrier. There, it potentially can inhibit PHD and cause HIFα stabilization through a pseudohypoxia pathway that does not require ROS (43, 44).”
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 [43]
In the citing paper
“We agree that increases in succinate represent an important contribution to the stabilization of HIFα in cells with Sdh inhibition (43).”
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 [43]
In the citing paper
“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 [384]
In the citing paper
“Loss-of-function mutations in SDH and FH cause a build-up of succinate and fumarate, respectively87. Accordingly, increased levels of succinate and fumarate caused by mutations in these genes can compete with αKG and inhibit activity of HIF hydroxylases and thus induce normoxic HIF1α activity in vitro88,89.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [88]
In the citing paper
“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 [185]
In the citing paper
“However, succinate is also an inhibitor of HIF-1α(213), which has been implicated in the exaggerated production of sFlt-1 and in the pathophysiology of preeclampsia(214, 215)”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [213]
In the citing paper
“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 [101]
In the citing paper
“Succinate was initially found to impair PHD2, the α-ketoglutarate-dependent enzyme regulating HIF stability, through product inhibition (Selak et al., 2005).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Selak et al., 2005
In the citing paper
“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 [66]
In the citing paper
“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 Selak et al., 2005
In the citing paper
“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 Selak et al., 2005
In the citing paper
“It should be noted that hypoxia and ischemia, as well as decreased oxidative phosphorylation, drive succinate accumulation in the mitochondrial matrix26,27.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [27]
In the citing paper
“Succinate inhibits the hydroxylation of HIF-1␣ by EGLN1, resulting in pseudohypoxic HIF-1␣ stabilization under normoxic conditions (10 -12).”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [10]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Di3 microscopy panel is described both with and without pVHL
MinorThe Figure 6A legend identifies panel v as the Di3 condition without pVHL. The results text instead describes the Di3 and Di4 comparisons in panels iv-vi as experiments cotransfected with HA-tagged pVHL, so the Di3 condition is inconsistent between the two descriptions.
“without pVHL (i, iii, v) or with pVHL (ii, iv, vi) together with one of the indicated siRNA constructs: scRNAi (i-iv), Di3 (v), or Di4 (vi).”
“When cells were cotransfected with GFP-ODD, HA-tagged pVHL, and Therefore, it is likely that in SDH-inhibited cells, the HIF-1␣ ODD domain is hydroxylated less efficiently, and consequently the either of the siRNA constructs, higher GFP levels were observed in Di3-and Di4-transfected cells compared to scRNAi-trans-binding of pVHL to GFP-ODD is reduced.”
Citations
Cites
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 · cited 1×
“In particular, elevated levels al., 2001; Jaakkola et al., 2001; Yu et al., 2001).”
BackgroundHIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
Ivan, 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 · cited 1×
“, facilitate HIF-2 (cid:1) degradation in these cells, despite the fact that PHD activity is inhibited. and ascorbate, it undergoes hydroxylation and migrates faster CANCER CELL : JANUARY 2005 on SDS-PAGE (Huang et al., 2002; Ivan et al., 2001).”
BackgroundEpstein, 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 · cited 1×
“The hydroxylases (HPH1-3 or PHD1-3) (Bruick and McKnight, 2001; Epstein et al., 2001; Ivan et al., 2002).”
A 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 · cited 1×
“The hydroxylases (HPH1-3 or PHD1-3) (Bruick and McKnight, 2001; Epstein et al., 2001; Ivan et al., 2002).”
Regulation of angiogenesis by hypoxia: role of the HIF system
Pugh, C. W., & Ratcliffe, P. J. (2003) · Nature Medicine · doi:10.1038/nm0603-677 · Cited by 2,520 · cited 11×
“) and ascorbate as cofactors (Kaelin, 2002; Scho-field and Zhang, 1999).”
BackgroundMethodInfluentialA model for p53-induced apoptosis
Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W., & Vogelstein, B. (1997) · Nature · doi:10.1038/38525 · Cited by 2,500 · cited 1×
“The tumor suppressor p53, which is known to elevate ROS production (Polyak et al., 1997), was used as a positive control.”
MethodOxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068
Chandel, N. S., McClintock, D. S., Feliciano, C. E., Wood, T. M., Melendez, J. A., Rodriguez, A. M., & Schumacker, P. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001914200 · Cited by 2,000 · cited 1×
“…c oxidase we found that hydrogen peroxide can induce HIF-1 (cid:1) levels as (complex IV), hence allocating more oxygen for PHD activity in was previously described (Chandel et al., 2000) (data not shown), we observed neither ROS generation nor a shift to a the cytosol (Hagen et al., 2003).”
BackgroundAsparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., & Whitelaw, M. L. (2002) · Science · doi:10.1126/science.1068592 · Cited by 1,558 · cited 1×
“The transcriptional activity of HIF-(cid:1) is also regulated by hydroxylation of an asparaginyl residue in its C-terminal transactivation domain in a reaction catalyzed by factor inhibiting HIF (FIH) (Hewitson et al., 2002; Lando et al., 2002a,2002b).”
BackgroundLando, D., Peet, D. J., Gorman, J. J., Whelan, D. A., Whitelaw, M. L., & Bruick, R. K. (2002) · Genes & Development · doi:10.1101/gad.991402 · Cited by 1,550
Flagged first, then by citations
2 of the 47 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Beasley, 2002, Hypoxia-inducible factors HIF-1α and HIF-2α in head and neck cancer, Cancer Res., 62, 2493
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Richter, S., Qin, N., Pacak, K., & Eisenhofer, G. (2013) · Advances in Pharmacology · doi:10.1016/b978-0-12-411512-5.00014-2 · Cited by 42
“The former accumulates in the cell when SDH is inhibited (Selak et al., 2005; Smith et al., 2007).”
BackgroundClinical and biochemical heterogeneity associated with fumarase deficiency
Ottolenghi, C., Hubert, L., Allanore, Y., Brassier, A., Altuzarra, C., Mellot‐Draznieks, C., Bekri, S., Goldenberg, A., Veyrieres, S., Boddaert, N., et al. (2011) · Human Mutation · doi:10.1002/humu.21534 · Cited by 43
“Proposed mechanisms for these tumors include apoptotic resistance, oxidative stress, and pseudohypoxic drive [Ratcliffe, 2007; Selak et al., 2005; Sudarshan et al., 2009].”
BackgroundGenetic causes of erythrocytosis and the oxygen-sensing pathway
Lee, F. S. (2008) · Blood Reviews · doi:10.1016/j.blre.2008.04.003 · Cited by 43
Hypoxia inducible factor (HIF) as a model for studying inhibition of protein–protein interactions
Burslem, G. M., Kyle, H. F., Nelson, A., Edwards, T. A., & Wilson, A. J. (2017) · Chemical Science · doi:10.1039/c7sc00388a · Cited by 39
Cilenti, L., Gregorio, J. D., Ambivero, C. T., Andl, T., Liao, R., & Zervos, A. S. (2020) · Scientific Reports · doi:10.1038/s41598-020-58484-8 · Cited by 44
Role of succinic acid in the regulation of sepsis
Liu, H., Zhang, H., Zhang, X., Chen, Q., & Xia, L. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109065 · Cited by 43
Itaconate controls its own synthesis via feedback-inhibition of reverse TCA cycle activity at IDH2
Heinz, A., Nonnenmacher, Y., Henne, A., Khalil, M., Bejkollari, K., Dostert, C., Hosseini, S., Goldmann, O., He, W., Palorini, R., et al. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166530 · Cited by 42
Stunted by Developing in Hypoxia: Linking Comparative and Model Organism Studies
Harrison, J. F., Shingleton, A. W., & Callier, V. (2015) · Physiological and Biochemical Zoology · doi:10.1086/682216 · Cited by 40
Toledo, R. A. (2017) · Endocrine Related Cancer · doi:10.1530/erc-16-0479 · Cited by 42
Sander, L. E., & Garaude, J. (2017) · Mitochondrion · doi:10.1016/j.mito.2017.10.008 · Cited by 41
Bailey, P. S. J., & Nathan, J. A. (2018) · Biomedicines · doi:10.3390/biomedicines6020060 · Cited by 41
“As previously discussed, somatic and germline mutations of SDH subunits are commonly identified in patients with paraganglioma [22,106,107], where the accumulation of succinate inhibits HIF prolyl hydroxylation, driving the expression of HIF target genes [30].”
BackgroundMetabolic Rewiring in Response to Biguanides Is Mediated by mROS/HIF-1a in Malignant Lymphocytes
Khan, H., Anshu, A., Prasad, A. K., Roy, S., Jeffery, J. J., Kittipongdaja, W., Yang, D. T., & Schieke, S. M. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.007 · Cited by 42
“treatment with hydrogen peroxide (H2O2) demonstrates the redox-dependent nature of HIF upregulation placing it downstream of mROS (Figures 3B and S3A) consistent with previously published data (Pan et al., 2007; Selak et al., 2005; Sullivan et al., 2013).”
BackgroundResultFletcher, S. C., & Coleman, M. L. (2020) · Biochemical Society Transactions · doi:10.1042/bst20190333 · Cited by 44
Targeted therapy in SDH- deficient GIST
Nannini, M., Rizzo, A., Indio, V., Schipani, A., Astolfi, A., & Pantaleo, M. A. (2021) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359211023278 · Cited by 41
NF-κB mediates aberrant activation of HIF-1 in malignant lymphoma
Qiao, Q., Nozaki, Y., Sakoe, K., Komatsu, N., & Kirito, K. (2010) · Experimental Hematology · doi:10.1016/j.exphem.2010.08.007 · Cited by 41
“In addition to these mechanisms, we cannot exclude the possibility that HIF-1a protein stability was also increased through pseudohypoxia caused by mutation of succinate dehydrogenase, resulting in the accumulation of succinate, which blocks HIF-1a prolyl-hydroxylase [25,26].”
BackgroundArcher, S. L. (2016) · Advances in experimental medicine and biology · doi:10.1007/978-1-4899-7678-9_3 · Cited by 41
Paranagama, M. P., Sakamoto, K., Amino, H., Awano, M., Miyoshi, H., & Kita, K. (2010) · Mitochondrion · doi:10.1016/j.mito.2009.12.145 · Cited by 40
Mitochondrial Metabolism in Melanoma
Huang, C. Y., Radi, R., & Arbiser, J. L. (2021) · Cells · doi:10.3390/cells10113197 · Cited by 40
“Because of its activity in inhibiting SDH, which catalyzes the conversion of succinate into fumarate, TRAP1 contributes to the stabilization of HIF1A via accumulation of succinate [41,128,129].”
BackgroundMetabolic Relationship Between Cancer-Associated Fibroblasts and Cancer Cells
Sazeides, C., & Le, A. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-65768-0_14 · Cited by 41
van Liere, E. L. S. A., van Dijk, L. J., Bosch, S., Vermeulen, L., Heymans, M. W., Burchell, G. L., de Meij, T. G. J., Ramsoekh, D., & de Boer, N. K. H. (2023) · European Journal of Cancer · doi:10.1016/j.ejca.2023.03.002 · Cited by 43
Unlocking potential: the role of the electron transport chain in immunometabolism
Zotta, A., O'Neill, L. A. J., & Yin, M. (2024) · Trends in Immunology · doi:10.1016/j.it.2024.02.002 · Cited by 47
Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme
Esteban-Amo, M. J., Jiménez-Cuadrado, P., Serrano‐Lorenzo, P., de la Fuente, M. Á., & Simarro, M. (2024) · Biomedicines · doi:10.3390/biomedicines12092050 · Cited by 51
IDH Mutations in Glioma: Molecular, Cellular, Diagnostic, and Clinical Implications
Choate, K. A., Pratt, E. P. S., Jennings, M. J., Winn, R. J., & Mann, P. B. (2024) · Biology · doi:10.3390/biology13110885 · Cited by 49
“In these instances, fumarate or succinate have been shown to inhibit α KG-dependent PHDs that target HIF-1 α for degradation [76,77], resulting in its subsequent accumulation.”
Metabolites as agents and targets for cancer immunotherapy
Trefny, M. P., Kroemer, G., Zitvogel, L., & Kobold, S. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01227-z · Cited by 57
“Loss-of-function mutation of succinate dehydrogenase similarly leads to the accumulation of succinate, which promotes cancer growth through inhibition of HIF1α hydroxylases 186 .”
Gerometabolites: The pseudohypoxic aging side of cancer oncometabolites
Menéndez, J. A., Alarcón, T., & Joven, J. (2014) · Cell Cycle · doi:10.4161/cc.28079 · Cited by 42
“1).(29-36) Succinate was initially found to impair PHD2, the α-ketoglutarate-dependent enzyme regulating HIFα stability, through product inhibition, and subsequent work confirmed that succinate could also inhibit the related enzyme PHD3.”
BackgroundLinehan, W. M., Srinivasan, R., & Garcia, J. A. (2013) · Seminars in Oncology · doi:10.1053/j.seminoncol.2013.05.009 · Cited by 42
Innate Immune Function of Mitochondrial Metabolism
Sancho, D., Enamorado, M., & Garaude, J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00527 · Cited by 40
“Succinate is accumulated in M1 mouse macrophages and was originally thought to stabilize HIF-1α through inhibition of prolyl hydroxylases (58).”
BackgroundAghamir, S. M. K., Heshmat, R., Ebrahimi, M., Ketabchi, S. E., Parichehreh-Dizaji, S., & Khatami, F. (2019) · OncoTargets and Therapy · doi:10.2147/ott.s207460 · Cited by 39
How DNA methylation affects the Warburg effect
Zhu, X., Xuan, Z., Chen, J., Li, Z., Zheng, S., & Song, P. (2020) · International Journal of Biological Sciences · doi:10.7150/ijbs.45420 · Cited by 42
“In addition, 2-hydroxyglutarate (2-HG) produced by IDH1/2 mutation [32], as well as the accumulation of succinate and fumarate caused by mutations in fumarate hydratase (FH) [78] and succinate dehydrogenase (SDH), can not only promote the Warburg effect by inhibiting the degradation of HIF [79], but also enhance the m…”
BackgroundRodrı́guez, C., Puente‐Moncada, N., Reiter, R. J., Sánchez‐Sánchez, A. M., Herrera, F., Rodríguez‐Blanco, J., Duarte‐Olivenza, C., Turos‐Cabal, M., Antolı́n, I., & Martı́n, V. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29886 · Cited by 40
Genetics of pheochromocytoma and paraganglioma
Wachtel, H., & Fishbein, L. M. (2021) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000634 · Cited by 41
“Loss-of-function mutations in SDHx genes lead to the accumulation of succinate and increased stability of HIFa, the common endpoint in pseudohypoxia-related tumors [18].”
BackgroundYebra, M., Bhargava, S., Kumar, A., Burgoyne, A. M., Tang, C.-M., Yoon, H., Banerjee, S., Aguilera, J., Cordes, T., Sheth, V. R., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2092 · Cited by 41
“Succinate inhibits a-ketoglutarate (a-KG)-dependent dioxygenases, including the HIF-prolyl 4-hydroxylases for hypoxia-inducible factor (HIF), which results in stabilization of HIF and in a “pseudo-hypoxic” state, that leads to upregulation of HIF-dependent targets (11, 15, 41, 42).”
BackgroundThe Role of Glucose Metabolism and Glucose-Associated Signalling in Cancer
Wittig, R., & Coy, J. F. (2007) · Perspectives in Medicinal Chemistry · doi:10.1177/1177391x0700100006 · Cited by 58
“…radiation (Moeller et al. 2004), reactive oxygen species (ROS) (Brunelle et al. 2005; Guzy et al. 2005; Mansfi eld et al. 2005) or simply the presence of pyruvate (Lu et al. 2002) or the tricarboxylic acid cycle (TCA) intermediates fumarate (Isaacs et al. 2005) and succinate (Selak et al. 2005).”
BackgroundBaysal, B. E., Lawrence, E. C., & Ferrell, R. E. (2007) · BMC Biology · doi:10.1186/1741-7007-5-12 · Cited by 39
“The paraganglia specificity of PGL tumors [4] and data from global gene-expression analysis [11], cell biology [12], animal-model studies [13], and gene-environment interaction and population genetics [14] support the hypothesis that constitutive hypoxic stimulation underlies the pathogenesis of PGL.”
BackgroundThe PLOD2/succinate axis regulates the epithelial–mesenchymal plasticity and cancer cell stemness
Tong, Y., Qi, Y., Xiong, G., Li, J., Scott, T. L., Chen, J., He, D., Li, L., Wang, C., Lane, A. N., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2214942120 · Cited by 43
The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer
Seyfried, T. N., Lee, D. C., Duraj, T., Ta, N. L., Mukherjee, P., Kiebish, M. A., Arismendi-Morillo, G., & Chinopoulos, C. (2025) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-025-10059-w · Cited by 45
“…to the transient extracellular accumulation of fermentation end products seen in oxygen deprived normal cells and tissues, many tumor cells chronically produce lactate and succinate even in the presence of oxygen (D. C. Lee et al. 2024; C. C. Kuo et al. 2022; Selak et al. 2005; Zhao et al. 2017).”
Huang, L., Yu, Z., Zhang, T., Zhao, X., & Huang, G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092949 · Cited by 39
“Mutations of key components of several signaling pathways and metabolic enzymes have been thought to play significant roles in cancer metabolic reprogramming [4,5].”
BackgroundSandulache, V. C., & Myers, J. N. (2011) · Head & Neck · doi:10.1002/hed.21664 · Cited by 38
Ezcurra, A. L. D. L., Bertolin, A. P., Kim, K., Katz, M. J., Gándara, L., Misra, T., Luschnig, S., Perrimon, N., Melani, M., & Wappner, P. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006073 · Cited by 36
“Another interesting example is the direct silencing of the succinate dehydrogenase complex subunit D (SDHD) by miR-210: inhibition of SDHD leads to accumulation of its substrate, succinate, which is in turn a product of HIFα prolyl hydroxylase (PHD) activity with inhibitory effects on the enzyme [62], which finally re…”
BackgroundMagnetic resonance spectroscopy of paragangliomas: new insights into in vivo metabolomics
Varoquaux, A. D., Fur, Y. L., Impériale, A., Reyre, A., Montava, M., Fakhry, N., Namer, I. J., Moulin, G., Pacák, K., Guye, M., et al. (2015) · Endocrine Related Cancer · doi:10.1530/erc-15-0246 · Cited by 39
New Insights into the Nuclear Imaging Phenotypes of Cluster 1 Pheochromocytoma and Paraganglioma
Taïeb, D., & Pacák, K. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.08.001 · Cited by 40
van Berkel, A., Vriens, D., Visser, E. P., Janssen, M. J. R., Gotthardt, M., Hermus, A. R., de Geus‐Oei, L., & Timmers, H. J. L. M. (2018) · Journal of Nuclear Medicine · doi:10.2967/jnumed.118.216796 · Cited by 39
“This finding is probably related to the fact that cluster 1 mutations result in an HIFdriven activation of the hypoxic–angiogenic pathway and metabolic shift toward aerobic glycolysis, known as the Warburg effect (16,27,28).”
BackgroundJiang, P., Huang, M., Qi, W., Wang, F., Yang, T., Gao, T., Luo, C., Deng, J., Yang, Z., Zhou, T., et al. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1414-6 · Cited by 38
Metabolic Drivers in Hereditary Cancer Syndromes
Sciacovelli, M., Schmidt, C., Maher, E. R., & Frezza, C. (2019) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030419-033612 · Cited by 39
“…associated with succinate accumulation in dSDH tumors was the stabilization of hypoxia-inducible factor 1 alpha (HIF1α) (Pollard et al. 2005a, Selak et al. 2005) due to the succinate-dependent inhibition of HIF prolyl-hydroxylases (PHDs), a group of proteins that belongs to the family of…”
BackgroundMetabolic Control of Smoldering Neuroinflammation
Peruzzotti‐Jametti, L., Willis, C. M., Hamel, R., Krzak, G., & Pluchino, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.705920 · Cited by 37
Dichloroacetate, the Pyruvate Dehydrogenase Complex and the Modulation of mESC Pluripotency
Rodrigues, A. S., Correia, M., Gomes, A. M., Pereira, S. L., Perestrelo, T., Sousa, M. I., & Ramalho‐Santos, J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0131663 · Cited by 39
“Curiously Hifs can be indirectly induced by succinate [46] and both have been implicated in the regulation of OCT4 [47].”
BackgroundA novel G106D alteration of the SDHD gene in a pedigree with familial paraganglioma
Ogawa, K., Shiga, K., Saijo, S., Ogawa, T., Kimura, N., & Horii, A. (2006) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.31444 · Cited by 37
“association with hypoxia, and the loss-of-function of this complex induces HIFs such as HIF1a, which would induce genes functioning to enable cells to survive [Baysal et al., 2002; Gottlieb and Tomlinson, 2005; Selak et al., 2005].”
BackgroundBartikoski, B. J., de Oliveira, M. S., Santo, R. C. D. E., dos Santos, L. P., dos Santos, N. G., & Xavier, R. M. (2022) · Metabolites · doi:10.3390/metabo12050394 · Cited by 38
“There are endogenous metabolites such as lipids, small peptides, amino acids, organic acids, vitamins, carbohydrates, thiols and nucleic acids; or from an exogenous source as drugs, environmental contaminants, food additives, toxins and other xenobiotics [23,24].”
BackgroundHIF1A-dependent induction of alveolar epithelial PFKFB3 dampens acute lung injury
Vohwinkel, C. U., Burns, N., Coit, E. J., Yuan, X., Vladar, E. K., Sul, C., Schmidt, E. P., Carmeliet, P., Stenmark, K. R., Nozik‐Grayck, E., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.157855 · Cited by 37
“Succinate has previously been shown to function as inhibitor of the prolyl hydroxylases (PHDs) (51), and can thereby function to promote the stabilization of HIF during normoxic conditions.”
Backgroundvan Spaendonck‐Zwarts, K. Y., Badeloe, S., Oosting, S. F., Hovenga, S., Semmelink, H. J. F., van Moorselaar, R. J. A., van Waesberghe, J. H., Mensenkamp, A. R., & Menko, F. H. (2011) · Familial Cancer · doi:10.1007/s10689-011-9491-5 · Cited by 37
Renal cell carcinoma: translational aspects of metabolism and therapeutic consequences
Yang, O. C. Y., Maxwell, P. H., & Pollard, P. J. (2013) · Kidney International · doi:10.1038/ki.2013.245 · Cited by 38
Cui, H., Grosso, S., Schelter, F., Mari, B. P., & Krüger, A. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00134 · Cited by 39
Contrasting clinical manifestations of SDHB and VHL associated chromaffin tumours
Srirangalingam, U., Khoo, B. C. E., Walker, L., MacDonald, F., Skelly, R. H., George, E., Spooner, D. A., Johnston, L., Monson, J. P., Grossman, A. B., et al. (2009) · Endocrine Related Cancer · doi:10.1677/erc-08-0239 · Cited by 38
“Firstly, inactivation of VHL and SDHB results in activation of hypoxic gene response pathways through stabilization of the HIF-1 and HIF-2 transcription factors (Maxwell et al. 1999, Selak et al. 2005).”
BackgroundJiang, Q., Zhang, Y., Zhou, Y., Hou, Y., Wang, J., Li, J., Li, M., Tong, H., & Lu, W. (2015) · PubMed Central · Cited by 38
Protein networks linking Warburg and reverse Warburg effects to cancer cell metabolism
Johar, D., Elmehrath, A. O., Khalil, R. M., Elberry, M. H., Zaky, S., Shalabi, S. A., & Bernstein, L. H. (2021) · BioFactors · doi:10.1002/biof.1768 · Cited by 42
“Certain types of head and neck squamous cell carcinomas (HNSCC) are sensitive to cetuximab as it downregulates LDHα and HIF-1α.”
BackgroundInfluentialWaldschmidt, J. M., Kloeber, J. A., Anand, P., Frede, J., Kokkalis, A., Dimitrova, V., Potdar, S. V., Nair, M. S., Vijaykumar, T., Im, N. G., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2040 · Cited by 38
Joshi, A., Ito, T., Picard, D., & Neckers, L. (2022) · Biomolecules · doi:10.3390/biom12070880 · Cited by 40
“Further, succinate accumulation inhibits hypoxia inducible factor (HIF) prolyl hydroxylation [91], stabilizing HIF1α [90] and creating a “pseudo-hypoxic” environment, which rewires cell metabolism towards glycolysis [90,92,93].”
BackgroundMacrophage immunometabolism dysregulation and inflammatory disorders
Pomeyie, K., Abrokwah, F. K., Boison, D., Amoani, B., Kyei, F., Adinortey, C. A., & Barnie, P. A. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118142 · Cited by 38
Crosstalk between oxygen- and nitric oxide-dependent signaling pathways in angiogenesis
Fraisl, P. (2013) · Experimental Cell Research · doi:10.1016/j.yexcr.2013.02.010 · Cited by 36
Prolyl hydroxylase domain enzymes and their role in cell signaling and cancer metabolism
Nguyen, T.-L., & Durán, R. V. (2016) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2016.09.026 · Cited by 40
A central role for hypoxia-inducible factor (HIF)-2α in hepatic glucose homeostasis
Ramakrishnan, S. K., & Shah, Y. M. (2017) · Nutrition and Healthy Aging · doi:10.3233/nha-170022 · Cited by 37
She, L., Xu, D., Wang, Z., Zhang, Y., Wei, Q., Aa, J., Wang, G., Liu, B., & Xie, Y. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2018.05.002 · Cited by 37
Targeting cancer's metabolic co-dependencies: A landscape shaped by genotype and tissue context
Bi, J., Wu, S., Zhang, W., & Mischel, P. S. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.05.002 · Cited by 37
McEvoy, C. R. E., Koe, L., Choong, D., Leong, H. S., Xu, H., Karikios, D. J., Plew, J. D., Prall, O. W. J., FELLOWES, A. P., & Fox, S. B. (2018) · npj Precision Oncology · doi:10.1038/s41698-018-0053-2 · Cited by 39
Metabolomics Profiling on Different Stages of Colorectal Cancer: A Systematic Review
Yusof, H. M., Rahim, S. A., Suddin, L. S., Saman, M. S. A., & Mazlan, M. (2018) · Malaysian Journal of Medical Sciences · doi:10.21315/mjms2018.25.5.3 · Cited by 37
Oudijk, L., Gaal, J., & de Krijger, R. R. (2018) · Endocrine Pathology · doi:10.1007/s12022-018-9555-2 · Cited by 37
Proline Hydroxylation Primes Protein Kinases for Autophosphorylation and Activation
Lee, S. B., Ko, A., Oh, Y. T., Shi, P., D’Angelo, F., Frangaj, B., Koller, A. A., Chen, E. I., Cardozo, T. J., Iavarone, A., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.06.021 · Cited by 38
“In this system, we incubated baculovirus-expressed GSTDYRK1A or GST-DYRK1B (Figure S1A) in the presence or absence of recombinant MYCtagged PHD1 in a reaction containing essential cofactors required for the enzymatic activity of PHD prolyl hydroxylases (Selak et al., 2005).”
MethodZhou, W., Zhao, Z., Yu, Z., Hou, Y., Keerthiga, R., & Fu, A. (2022) · Mitochondrion · doi:10.1016/j.mito.2022.04.004 · Cited by 40
Ooi, A., & Furge, K. A. (2012) · 癌症：英文版 · doi:10.5732/cjc.012.10102 · Cited by 38
Mitochondrial superoxide anion (O2·-) inducible "mev-1" animal models for aging research
Ishii, T., Miyazawa, M., Hartman, P. S., & Ishii, N. (2011) · BMB Reports · doi:10.5483/bmbrep.2011.44.5.298 · Cited by 38
“to changes in cellular metabolism, angiogenesis, cell scattering and cell proliferation that could result in tumorigenesis (56, 57, 69) (Fig.”
BackgroundRegulated Function of the Prolyl-4-Hydroxylase Domain (PHD) Oxygen Sensor Proteins
Nytko, K. J., Spielmann, P., Camenisch, G., Wenger, R. H., & Stiehl, D. P. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1683 · Cited by 37
“Endogenous tricarboxylic acid cycle intermediates and reactive oxygen species (ROS) have been reported to inhibit PHD function and hence link mitochondrial function with PHD-dependent oxygen sensing (12, 15, 43, 48).”
InfluentialMitochondria: Oxygen sinks rather than sensors?
Wenger, R. H. (2005) · Medical Hypotheses · doi:10.1016/j.mehy.2005.08.047 · Cited by 36
“tumor suppressors, consistent with a constitutive HIFα activation in cancer cells with inactivation mutations of these tumor suppressors [38-40].”
BackgroundMetabolism Shapes Immune Responses to Staphylococcus aureus
Arumugam, P., & Kielian, T. (2023) · Journal of Innate Immunity · doi:10.1159/000535482 · Cited by 39
“For example, succinate and α -ketoglutarate inhibit prolyl hydroxylases, proteins that bind the transcription factor HIF-1a, and promote its degradation under normoxia [123, 124].”
BackgroundWang, M., Flaswinkel, H., Joshi, A., Napoli, M., Masgrau‐Alsina, S., Kamper, J. M., Henne, A., Heinz, A., Bérouti, M., Schmacke, N. A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50104-7 · Cited by 37
HIF–prolyl hydroxylases and cardiovascular diseases
Banerjee, S. S., Thirunavukkarasu, M., Rishi, M. T., Sánchez, J. A., Maulik, N., & Maulik, G. (2012) · Toxicology Mechanisms and Methods · doi:10.3109/15376516.2012.673088 · Cited by 37
“Mutation in the gene succinate dehydrogenase leads to accumulation of succinate which in turn, inhibits PHD activity (Lee et al. 2005; Selak et al. 2005).”
BackgroundStructural and functional consequences of succinate dehydrogenase subunit B mutations
Kim, E., Rath, E. M., Tsang, V., Duff, A. P., Robinson, B. G., Church, W. B., Benn, D. E., Dwight, T., & Clifton-Bligh, R. J. (2015) · Endocrine Related Cancer · doi:10.1530/erc-15-0099 · Cited by 39
Daniel, E., Jones, R. N., Bull, M., & Newell-Price, J. D. C. (2016) · European Journal of Endocrinology · doi:10.1530/eje-16-0595 · Cited by 36
Nguyen, T. D., Prykhodko, O., Hållenius, F. F., & NYMAN, M. E. (2017) · Journal of Nutritional Science · doi:10.1017/jns.2017.54 · Cited by 36
“Due to its activation on the transcriptional factor hypoxia-inducible factor 1α in both tumours and inflammatory states, succinic acid has been proposed as a signal linking inflammation and cancer((52,56,57)).”
BackgroundKitajima, S., Lee, K. L., Hikasa, H., Sun, W., Huang, R. Y., Yang, H. H., Matsunaga, S., Yamaguchi, T., Araki, M., Kato, H., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.23010 · Cited by 36
“Of note, during the disposal of ammonia by GS, cataplerotic reactions remove α-KG from the TCA cycle [32, 40], which may lead to disturbed TCA cycle and transient accumulations of TCA cycle intermediates that cause HIF-1α stabilization [36].”
BackgroundToledo, R. A., & Jiménez, C. (2018) · F1000Research · doi:10.12688/f1000research.13995.1 · Cited by 35
Kolasińska-Ćwikła, A., Pęczkowska, M., Ćwikła, J. B., et al. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8070952 · Cited by 36
Cell Intrinsic and Systemic Metabolism in Tumor Immunity and Immunotherapy
Coleman, M. F., Cozzo, A. J., Pfeil, A. J., Etigunta, S. K., & Hursting, S. D. (2020) · Cancers · doi:10.3390/cancers12040852 · Cited by 37
“HIF-1α also increases both the number and suppressive properties of Tregs via the upregulation of FOXP3 [200,201].”
BackgroundInfluentialEpigenetic and metabolic reprogramming of SDH-deficient paragangliomas
Moog, S., Lussey‐Lepoutre, C., & Favier, J. (2020) · Endocrine Related Cancer · doi:10.1530/erc-20-0346 · Cited by 42
DJ-1: A promising therapeutic candidate for ischemia-reperfusion injury
Lazzari, F. D., Prag, H. A., Gruszczyk, A. V., Whitworth, A. J., & Bisaglia, M. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101884 · Cited by 36
“During hypoxia, succinate plays a role in HIF1-α stabilization as it is also transported to the cytosol, where it can inhibit PHDs [69,70].”
Oncometabolites—A Link between Cancer Cells and Tumor Microenvironment
Baryła, M., Semeniuk-Wojtaś, A., Róg, L., Kraj, L., Małyszko, M., & Stec, R. (2022) · Biology · doi:10.3390/biology11020270 · Cited by 40
“However, some data suggest that fumarate, similarly to succinate, reduces levels of TET1 and TET2 mRNA, leading to DNA demethylation and a reduction in global 5-hmC levels, resulting in decreased expression of some HIF target genes [61].”
BackgroundNaidu, S. A. G., Clemens, R., & Naidu, A. S. (2022) · Journal of Dietary Supplements · doi:10.1080/19390211.2022.2075072 · Cited by 40
Bock, K. D., Smet, F. D., de Oliveira, R. L., Anthonis, K., & Carmeliet, P. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0482-z · Cited by 39
“In addition to HIF-α, PHDs and FIH also hydroxylate other proteins, some of which are associated with angiogenesis [18].”
BackgroundInfluentialSchaefer, I., Hornick, J. L., & Bovée, J. V. M. G. (2018) · Laboratory Investigation · doi:10.1038/s41374-017-0003-6 · Cited by 36
“been observed in SDH- and FH-deficient tumors [4, 103].”
Recent Insights into the Molecular Pathogenesis of Pheochromocytoma and Paraganglioma
Nakamura, E., & Kaelin, W. G. (2006) · Endocrine Pathology · doi:10.1385/ep:17:2:97 · Cited by 36
Three autocrine feedback loops determine HIF1α expression in chronic hypoxia
Qutub, A. A., & Popel, A. S. (2007) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2007.07.004 · Cited by 37
“One in vitro study estimated ∼500 μM succinate is produced in cells, where SDH was inhibited [ 23 ].”
BackgroundMethodInfluentialChen, M., Chen, Y., Zhu, W., Yan, X., Jing, X., Zhang, P., Liu, P., & Li, P. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115088 · Cited by 36
Andreyev, A. Y., Yang, H., Doulias, P., Dolatabadi, N., Zhang, X., Luevanos, M., Blanco, M., Baal, C., Putra, I., Nakamura, T., et al. (2024) · Advanced Science · doi:10.1002/advs.202306469 · Cited by 35
Metabolic Roles of HIF1, c-Myc, and p53 in Glioma Cells
Trejo‐Solís, C., Castillo‐Rodríguez, R. A., Serrano-García, N., Silva‐Adaya, D., Vargas-Cruz, S., Chávez-Cortéz, E. G., Gallardo‐Pérez, J. C., Zavala-Vega, S., Cruz-Salgado, A., & Magaña-Maldonado, R. (2024) · Metabolites · doi:10.3390/metabo14050249 · Cited by 41
“…of prolyl dehydrogenase, resulting in succinate accumulation, or indirectly by ROS generation due to a defect in mitochondrial complex II [181,250]. miR-448 has been shown to inhibit proliferation, migration, and invasion while increasing radiosensitivity in vitro and in vivo in glioma…”
BackgroundPhosphoglycerate Dehydrogenase: Potential Therapeutic Target and Putative Metabolic Oncogene
Zogg, C. K. (2014) · Journal of Oncology · doi:10.1155/2014/524101 · Cited by 36
Genetics of Familial Renal Cancers
Maher, E. R. (2010) · Nephron Experimental Nephrology · doi:10.1159/000320892 · Cited by 35
MicroRNA regulation of cancer metabolism: role in tumour suppression
Tomasetti, M., Santarelli, L., Neužil, J., & Dong, L. (2014) · Mitochondrion · doi:10.1016/j.mito.2014.06.004 · Cited by 36
“have been identified as inhibitors of all three PHDs (Selak et al., 2005).”
BackgroundCurrent views on cell metabolism in SDHx-related pheochromocytoma and paraganglioma
Vícha, A., Taïeb, D., & Pacák, K. (2014) · Endocrine Related Cancer · doi:10.1530/erc-13-0398 · Cited by 35
“…and coordinated suppression of oxidoreductase enzymes, all processes that would be directly or indirectly regulated by the activation of HIF1a and/or HIF2a (Dahia et al. 2005, Selak et al. 2005, Mole et al. 2009, Favier & Gimenez-Roqueplo 2010, Semenza 2010, 2011, 2012, Keith et al. 2012).”
Nanoformulations of Albendazole As Effective Anticancer and Antiparasite Agents
Movahedi, F., Li, L., Gu, W., & Xu, Z. P. (2017) · Nanomedicine · doi:10.2217/nnm-2017-0102 · Cited by 34
Kľučková, K., Thakker, A., Vettore, L. A., Escribano-Gonzalez, C., Hindshaw, R. L., Tearle, J. L. E., Goncalves, J., Kaul, B., Lavery, G. G., Favier, J., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201901456r · Cited by 36
Lussey‐Lepoutre, C., Bellucci, A., Burnichon, N., Amar, L., Buffet, A., Drossart, T., Fontaine, S., Clémеnt, O., Bénit, P., Rustin, P., et al. (2019) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-019-04633-9 · Cited by 34
Metadata
- Authors
- 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.
- Affiliations
- Cancer Research UK (GB)
- University of Pennsylvania (US)
- University of Strathclyde (GB)
- Corresponding author
- Gottlieb, Eyal
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 7
- Issue
- 1
- Pages
- 77-85
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2057199368
- Cited by
- 2,108
- References
- 47
- Citations by year
- 2026: 110 · 2025: 115 · 2024: 97 · 2023: 97 · 2022: 116 · 2021: 139 · 2020: 128 · 2019: 123 · 2018: 93 · 2017: 107 · 2016: 110 · 2015: 107 · 2014: 108 · 2013: 109 · 2012: 86
- FWCI
- 26.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Strathprints: The University of Strathclyde institutional repository (University of Strathclyde) (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- Beatson Institute for Cancer Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Ear and Head Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Keywords
- succinic acid, succinate dehydrogenase, HIF-1α, prolyl hydroxylase, mitochondrial dysfunction, tumor suppressor proteins, carcinogenesis, VHL, tumor angiogenesis, fumarate hydratase
- MeSH terms
- Animals, Cell Line, Cell Transformation, Neoplastic, Citric Acid Cycle, Enzyme Activation, Humans, Mitochondria, Oncogenes, Procollagen-Proline Dioxygenase, Succinate Dehydrogenase, Transcription Factors, Signal Transduction, Gene Expression Regulation, Enzymologic, Reactive Oxygen Species, Succinic Acid, Tumor Suppressor Proteins, RNA, Small Interfering, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
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.
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