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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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16 Own result · 3 No full text of the sources · 3 Own interpretation · 1 Supported so far · 1 Own method · 1 No basis given
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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- 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
boosteddirect- Asserted: passes — The authors put it forward as true.
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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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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
plain- Asserted: passes — The authors put it forward as true.
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It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ 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
“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).”
§ 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
“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
Research works printed but not linked: 1
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Sorted by citations
Items 1,101–1,200 of 2,106
Euceda, L. R., Haukaas, T. H., Giskeødegård, G. F., Vettukattil, R., Engel, J., Silwal‐Pandit, L., Lundgren, S., Borgen, E., Garred, Ø., Postma, G., et al. (2017) · Metabolomics · doi:10.1007/s11306-017-1168-0 · Cited by 29
“Succinate is the substrate of succinate dehydrogenase (SDH), a tricarboxylic acid (TCA) cycle enzyme which has been identified as a tumor suppressor (Selak et al. 2005).”
BackgroundMori, M. P., Costa, R. A. P. E., Soltys, D. T., Freire, T. D. S., Rossato, F. A., Amigo, I., Kowaltowski, A. J., Vercesi, A. E., & de Souza-Pinto, N. C. (2017) · Scientific Reports · doi:10.1038/s41598-017-00130-x · Cited by 28
Wang, Q., Shen, W.-L., Liu, C., Mu, D.-L., Wu, X., Guo, N.-G., & Zhu, J. (2017) · Chemosphere · doi:10.1016/j.chemosphere.2017.06.043 · Cited by 27
Glod, J. W., Arnaldez, F. I., Wiener, L. S., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0986 · Cited by 29
“Vandetanib (CAPRELSA; ZD6474; Sanofi Genzyme) is a small-molecule receptor tyrosine kinase inhibitor, given as a once-daily oral drug that inhibits VEGFR2and EGFR-dependent signaling.”
BackgroundInfluentialClinical and Molecular Update on Genetic Causes of Pituitary Adenomas
Vasilev, V., Daly, A., Zacharieva, S., & Beckers, A. M. (2020) · Hormone and Metabolic Research · doi:10.1055/a-1143-5930 · Cited by 30
Testa, U., Pelosi, E., & Castelli, G. (2020) · Medicines · doi:10.3390/medicines7080044 · Cited by 30
“Thus, succinate deregulates the HIF pathway through a direct inhibition of prolyl hydroxylases (PHDs), targeting HIF for degradation [56].”
BackgroundPrecision Surgery and Kidney Cancer: Knowledge of Genetic Alterations Influences Surgical Management
Gomella, P. T., Linehan, W. M., & Ball, M. W. (2021) · Genes · doi:10.3390/genes12020261 · Cited by 29
“Without a functioning SDH complex, succinate accumulates which leads to stabilization of HIF1a [37], creating a pseudohypoxic state and an increase in aerobic glycolysis similar to what is seen in HLRCC-associated tumors.”
BackgroundInfluentialPheochromocytoma: Gasping for Air
Jochmanová, I., Zhuang, Z., & Pacák, K. (2015) · Hormones and Cancer · doi:10.1007/s12672-015-0231-4 · Cited by 30
Differential metabolic consequences of fumarate hydratase and respiratory chain defects
Raimundo, N., Ahtinen, J., Fumić, K., Barić, I., Remes, A. M., Renkonen, R., Lapatto, R., & Suomalainen, A. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.01.008 · Cited by 30
No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome
Vahteristo, P., Koski, T. A., Näätsaari, L., Kiuru, M. H., Karhu, A., Herva, R., Sallinen, S., Kuismin, O., Björck, E., Richard, S., et al. (2009) · Familial Cancer · doi:10.1007/s10689-009-9312-2 · Cited by 29
Holt, D. E., Henthorn, P. S., Howell, V. M., Robinson, B. G., & Benn, D. E. (2014) · Journal of Comparative Pathology · doi:10.1016/j.jcpa.2014.03.007 · Cited by 29
Bell, E. L., Klimova, T. A., & Chandel, N. S. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1655 · Cited by 29
“Further studies must address the relation between mitochondrial ROS and PHDs. Recent reports indicate that levels of TCA intermediates can regulate the ability of the PHDs to hydroxylate HIF (cid:2) (21, 29, 42, 48).”
Succinate dehydrogenase complex subunit C: Role in cellular physiology and disease
Wang, Q., Li, M., Zeng, N., Zhou, Y., & Yan, J. (2023) · Experimental Biology and Medicine · doi:10.1177/15353702221147567 · Cited by 30
Shen, T., Wang, H., Tang, B., Zhu, G., & Wang, X. (2023) · RNA Biology · doi:10.1080/15476286.2023.2216562 · Cited by 29
Luo, H., Wang, Q., Yang, F., Liu, R. R., Gao, Q., Cheng, B., Lin, X., Huang, L., Chen, C., Jin, X., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.164968 · Cited by 39
Kumar, M., Sharma, S., Kumar, J., Barik, S., & Mazumder, S. (2024) · Current Research in Immunology · doi:10.1016/j.crimmu.2024.100077 · Cited by 28
“Succinate is transported into the cytosol, where it impairs prolyl hydroxylase (PHD) activity, stabilizing and activating HIF-1 α (Selak et al., 2005) and triggering pseudo-hypoxia.”
BackgroundInfluentialTargeting valine catabolism to inhibit metabolic reprogramming in prostate cancer
Bidgood, C. L., Philp, L., Rockstroh, A., et al. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06893-2 · Cited by 28
“All cells were cultured between passage number 20 – 40 and their medium replenished every 48 – 72 h. Cells were routinely screened for mycoplasma using the Translational Research Institute ’ s routine mycoplasma testing service and originally STR pro fi led by the QUT Genomics Research Centre.”
Fisher, R. A., Larkin, J., & Swanton, C. (2011) · The EPMA Journal · doi:10.1007/s13167-011-0137-3 · Cited by 28
“Similar to the pathogenic role of mutations in the isocitrate dehydrogenase metabolic enzymes (IDH1 and IDH2) in some gliomas, these mutant metabolic enzymes inhibit prolylhydroxylases in the cell cytosol, which leads to stabilisation of HIF1-alpha and activation [47-49].”
BackgroundHypoxia and Hormone-Mediated Pathways Converge at the Histone Demethylase KDM4B in Cancer
Yang, J., Harris, A. L., & Davidoff, A. M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19010240 · Cited by 30
“, 2-hydroxyglutarate [24], succinate [25], and fumarate [26]).”
Endothelial metabolism in pulmonary vascular homeostasis and acute respiratory distress syndrome
Stevens, R. P., Paudel, S. S., Johnson, S., Stevens, T., & Lee, J. (2021) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00131.2021 · Cited by 32
Genomic and Metabolic Hallmarks of SDH- and FH-deficient Renal Cell Carcinomas
Yoo, A., Tang, C., Zucker, M. R., Fitzgerald, K. N., DiNatale, R. G., Rappold, P. M., Weiss, K. L., Freeman, B., Lee, C., Schultz, N. D., et al. (2022) · European Urology Focus · doi:10.1016/j.euf.2021.12.002 · Cited by 29
“FH and SDH have also been shown to regulate HIF-alpha prolyl hydroxylases, thereby leading to stabilization and activation of HIF-1 alpha [32], [33].”
BackgroundLöffler, J., Noom, A., Ellinghaus, A., Dienelt, A., Kempa, S., & Duda, G. N. (2023) · Communications Biology · doi:10.1038/s42003-023-04652-1 · Cited by 35
Oxygen Sensing: A Common Crossroad in Cancer and Neurodegeneration
Quaegebeur, A., & Carmeliet, P. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_83 · Cited by 27
“The molecular mechanism underlying this tumor susceptibility partly involves “product inhibition” by accumulation of succinate or the structural homologous fumarate (Isaacs et al. 2005; Selak et al. 2005).”
BackgroundRegulation of Renal Cell Carcinoma Cell Proliferation, Invasion and Metastasis by Connexin 32 Gene
Sato, H., Hagiwara, H., Ohde, Y., Senba, H., Virgona, N., & Yano, T. (2007) · The Journal of Membrane Biology · doi:10.1007/s00232-007-9020-5 · Cited by 28
“When FH inhibition occurs in tumor tissues, the substrate of FH, fumarate, accumulates in mitochondria and subsequently leaks out to the cytosol, where it inhibits a family of prolyl hydroxylase enzymes (Selak et al., 2005).”
BackgroundMontez, P., Vázquez‐Medina, J. P., Rodríguez, R., Thorwald, M. A., Viscarra, J. A., Lam, L., Peti‐Peterdi, J., Nakano, D., Nishiyama, A., & Ortiz, R. M. (2012) · Endocrinology · doi:10.1210/en.2012-1390 · Cited by 31
“) (31, 42) is not well defined, but the scarce, available data, including this study, suggest that it contributes in some capacity, potentially through its recently discovered receptor, GPR91 (G protein-coupled metabolic receptor 91) (42, 51).”
BackgroundThe Mitochondrial Warburg Effect: A Cancer Enigma
Kim, H. H., Kim, T., Kim, E., et al. (2009) · Interdisciplinary Bio Central · doi:10.4051/ibc.2009.2.0007 · Cited by 28
“For example, mutations of two metabolic enzymes, succinate dehydrogenase and fumarate hydratase, were shown to induce severe tumorigenesis (Selak et al., 2005).”
BackgroundYu, W., He, X., Ni, Y., Ngeow, J. Y. Y., & Eng, C. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu425 · Cited by 28
“In addition, dysfunction of SDH in the tricarboxylic acid cycle inhibits prolyl-hydroxylation of HIF-1a and HIF-2a, which is an important step for their degradation (28).”
BackgroundHagland, H. R., Nikolaisen, J., Hodneland, L., Gjertsen, B. T., Bruserud, Ø., & Tronstad, K. J. (2007) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.11.8.1055 · Cited by 27
“A HIF-1 α -stabilising mitochondrion-to-cytosol pathway has been described that may have implications for oncogenesis [75] .”
BackgroundCafeo, G., Kohnke, F. H., Mezzatesta, G., et al. (2015) · Chemistry - A European Journal · doi:10.1002/chem.201406183 · Cited by 28
Abdel-Hamid, N., Ramadan, M., & Amgad, S. W. (2013) · American Journal of Cancer Prevention · doi:10.12691/ajcp-1-2-1 · Cited by 28
Schneider, M., Harnoss, J. M., Strowitzki, M. J., Radhakrishnan, P., Platzer, L. K., Harnoss, J. C., Hank, T. P., Cai, J., & Ulrich, A. B. (2015) · Hypoxia · doi:10.2147/hp.s60872 · Cited by 26
“However, crystallographic and sequence analyses revealed that the active site is highly conserved among PHDs and FIH, thus hampering the development of isoform-specific PHI.”
Kaluz, Š., Kaluzová, M., & Stanbridge, E. J. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21644 · Cited by 27
“Dysfunctional succinate dehydrogenase (various subunits) and fumarate hydratase cause accumulation of succinate and fumarate, respectively, and both substances act as competitive inhibitors for 2OG [Isaacs et al., 2005; Selak et al., 2005].”
BackgroundProchilo, T., Savelli, G., Bertocchi, P., et al. (2013) · Case Reports in Oncology · doi:10.1159/000348429 · Cited by 27
G protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases
Hu, J., Li, T., Du, X., Wu, Q. E., & Le, Y.-Z. (2017) · Vision Research · doi:10.1016/j.visres.2017.05.001 · Cited by 26
Weber, A., Klocker, H., Oberacher, H., Gnaiger, E., Neuwirt, H., Sampson, N., & Eder, I. E. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19072129 · Cited by 26
“Since high lactate levels can induce intracellular acidification, which subsequently increases succinate uptake and leads to a stabilization of HIF-1α [7,11], we examined HIF-1α levels by immunofluorescence.”
BackgroundMetabolic ROS Signaling: To Immunity and Beyond
Andreyev, A. Y., Kushnareva, Y. E., Starkova, N. N., & Starkov, A. A. (2020) · Biochemistry (Moscow) · doi:10.1134/s0006297920120160 · Cited by 28
Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells
Silva, A. C. B. S., Pérez-Valencia, J. A., Sciacovelli, M., Lalou, C., Sarlak, S., Tronci, L., Nikitopoulou, E., Mészáros, A., Frezza, C., Rossignol, R., et al. (2021) · Cancers · doi:10.3390/cancers13071727 · Cited by 28
“This accumulation leads to transmission of an “oncogenic” signal from mitochondria to the cytosol, where the hypoxia inducible factor 1α (HIF-1α) prolyl hydroxylases (PHDs) are inhibited [12].”
BackgroundSignals from the Circle: Tricarboxylic Acid Cycle Intermediates as Myometabokines
Maurer, J., Hoene, M., & Weigert, C. (2021) · Metabolites · doi:10.3390/metabo11080474 · Cited by 27
“A transcriptome analysis of livers of exercising mice pointed to HIF1α and cAMP as positive regulators of the acute transcriptional response to endurance exercise [39].”
BackgroundRed Blood Cell Metabolism in Pyruvate Kinase Deficient Patients
Roy, M. K., Cendali, F. I., Ooyama, G., Gamboni, F., Morton, H. D., & D’Alessandro, A. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.735543 · Cited by 27
Zhu, S., Gu, H., Peng, C. Y., Xia, F., Cao, H., & Cui, H. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.849625 · Cited by 30
Tumorigenesis Mechanisms Found in Hereditary Renal Cell Carcinoma: A Review
Webster, B. R., Gopal, N., & Ball, M. W. (2022) · Genes · doi:10.3390/genes13112122 · Cited by 28
“Succinate accumulation in the mitochondrial matrix is thought to inhibit proline hydroxylase (PHD) of HIF and thus the loss of VHL-mediated degradation of HIF [116].”
BackgroundEmerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases
Wang, S., Kang, Y., Wang, R., Deng, J., Yu, Y., Yu, J. J., & Wang, J. (2022) · Molecules · doi:10.3390/molecules27248754 · Cited by 28
Succinate mediates inflammation-induced adrenocortical dysfunction
Mateska, I., Witt, A., Hagag, E., Sinha, A. N., Yılmaz, C., Thanou, E., Sun, N., Kolliniati, O., Patschin, M., Abdelmegeed, H., et al. (2023) · eLife · doi:10.7554/elife.83064 · Cited by 26
Pino, E. C., Wang, H., McDonald, M. E., Qiang, L., & Farmer, S. R. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.350918 · Cited by 27
“In fact, the absence of thewell established tumor suppressors succinate dehydrogenase and fumarate hydratase has been linked to tumor progression as a result of activation of the HIF pathway and angiogenesis (16, 17).”
BackgroundMitochondrial disorders in renal tumors
Hervouet, É., & Godinot, C. (2006) · Mitochondrion · doi:10.1016/j.mito.2006.03.003 · Cited by 27
Fábián, Z., Taylor, C. T., & Nguyen, L. K. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1383-6 · Cited by 28
“Indeed, loss-of-function mutations in succinate dehydrogenase were found to be inhibitory towards PHDs leading to the stabilisation of HIF-α subunits and succinate was identified as the mediator of this effect [30, 31].”
BackgroundPossible modifier genes in the variation of neurofibromatosis type 1 clinical phenotypes
Sharafi, P., & Ayter, Ş. (2018) · Journal of Neurogenetics · doi:10.1080/01677063.2018.1456538 · Cited by 26
“This effect is initiated by the induction of hypoxia-inducible transcription factor-1 (HIF1), which is activated by hypoxia together with the accumulation of succinate and fumarate, the Krebs cycle metabolites (Selak et al., 2005).”
BackgroundYao, L., Barontini, M., Niederle, B., Jech, M., Pfragner, R., & Dahia, P. L. M. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2245 · Cited by 27
Reprogramming of tumor-associated macrophages by metabolites generated from tumor microenvironment
Kim, S. W., Kim, C. W., Moon, Y.-A., & Kim, H. S. (2024) · Animal Cells and Systems · doi:10.1080/19768354.2024.2336249 · Cited by 28
“Within cells, succinate stabilizes and activates HIF-1α by competing with ketoglutarate to inhibit HIF–prolyl hydroxyl-ase activity (Selak et al. 2005).”
Tiwari, R., Sharma, R., Rajendran, G., Borkowski, G. S., An, S. Y., Schonfeld, M. P., O’Sullivan, J., Schipma, M. J., Zhou, Y., Courbon, G., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci176207 · Cited by 35
“For example, succinate, a TCA cycle metabolite known to accumulate with IRI, can inhibit all 3 PHDs (41, 42).”
Metabolic Signaling in the Tumor Microenvironment
Clay, R., Li, K., & Jin, L. (2025) · Cancers · doi:10.3390/cancers17010155 · Cited by 31
The flux of energy in critical illness and the obesity paradox
Jaitovich, A., & Hall, J. B. (2025) · Physiological Reviews · doi:10.1152/physrev.00029.2024 · Cited by 34
BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation
Kim, S., Choi, C., Son, Y., Lee, J., Joo, S., & Lee, Y. (2025) · Autophagy · doi:10.1080/15548627.2025.2487035 · Cited by 34
“The glycolytic shift stabilizes HIF1A by inhibiting prolyl hydroxylase domain (PHD) enzymes through succinate accumulation from enhanced glycolysis [44].”
Genetics of Gastrointestinal Stromal Tumors
Patil, D. T., & Rubin, B. P. (2015) · Surgical pathology clinics · doi:10.1016/j.path.2015.05.006 · Cited by 26
“In addition, succinate inhibits hypoxia-inducible factor 1 alpha (HIF-1a)prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1a.(36) More recently, it was shown that SDH-deficient GISTs arise as a result of a failure in TET2 maintenance demethylation.”
BackgroundWang, X., Guo, X., Yu, W., Li, C., Gui, Y., & Cai, Z. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-196 · Cited by 26
“The mutations of FH and SDH are associated with dysfunction of tricarboxylic acid cycle [9,10].”
How best to manage gastrointestinal stromal tumor
Lanke, G., & Lee, J. H. (2017) · World Journal of Clinical Oncology · doi:10.5306/wjco.v8.i2.135 · Cited by 26
Sodium dehydroacetate exposure decreases locomotor persistence and hypoxia tolerance in zebrafish
Huang, X., Zhao, X., Zhu, K., Ding, S., & Shao, B. (2020) · Environmental Research · doi:10.1016/j.envres.2020.110276 · Cited by 25
Yamazaki, Y., Gao, X., Pecori, A., Nakamura, Y., Tezuka, Y., Omata, K., Ono, Y., Morimoto, R., Satoh, F., & Sasano, H. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.587769 · Cited by 30
Loss of SDHB Induces a Metabolic Switch in the hPheo1 Cell Line toward Enhanced OXPHOS
Tabebi, M., Dutta, R. K., Skoglund, C., Söderkvist, P., & Gimm, O. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23010560 · Cited by 27
Succinate: A Novel Mediator to Promote Atherosclerotic Lesion Progression
Zhang, S., Liang, Y., Lü, L., Chen, Y., Wu, P., & Wei, D. (2022) · DNA and Cell Biology · doi:10.1089/dna.2021.0345 · Cited by 27
“Studies showed that the accumulation of succinate leads to the accumulation of HIF-1 a and the enhancement of its transcriptional activity (Selak et al. , 2005).”
Celada, L., Cubiella, T., San‐Juan‐Guardado, J., Gutiérrez, G., Beiguela, B., Rodríguez, R. Q., Poch, M., Astudillo, A., Grijalba, A., Sobrino, P. S., et al. (2022) · The Journal of Pathology · doi:10.1002/path.6026 · Cited by 30
“Further, increased intracellular levels of the succinate oncometabolite, due to SDH loss of function, reduces PHD activity, induces the abnormal stabilization of HIFα in normoxia, and upregulates expression of HIF-target genes [5].”
BackgroundThe Immune Landscape of Pheochromocytoma and Paraganglioma: Current Advances and Perspectives
Uher, O., Vanova, K. H., Taïeb, D., Calsina, B., Robledo, M., Clifton-Bligh, R. J., & Pacák, K. (2024) · Endocrine Reviews · doi:10.1210/endrev/bnae005 · Cited by 31
A Role for Saccharomyces cerevisiae Tpa1 Protein in Direct Alkylation Repair
Shivange, G., Kodipelli, N., Mohan, M., & Anindya, R. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.590216 · Cited by 26
“Hypoxic solid tumors also accumulate fumarate and/or succinate, which act as 2-oxoglutarate analogs and inhibit HIF prolylhydroxylase (67, 68).”
BackgroundRole of microenvironment on neuroblastoma SK-N-AS SDHB-silenced cell metabolism and function
Rapizzi, E., Fucci, R., Giannoni, E., Canu, L., Richter, S., Cirri, P., & Mannelli, M. (2015) · Endocrine Related Cancer · doi:10.1530/erc-14-0479 · Cited by 26
“…the finding that succinate accumulation inhibits prolyl-hydroxylase activity and reduces HIF degradation (Dahia et al. 2005, Pollard et al. 2005, Selak et al. 2005, Koivunen et al. 2007, Favier et al. 2009, and, for recent reviews, see Richter et al. (2013) and Jochmanová et al. (2014)), we…”
BackgroundComplex role of the HIF system in cardiovascular biology
Czibik, G. (2010) · Journal of Molecular Medicine · doi:10.1007/s00109-010-0646-x · Cited by 27
Genetic Kidney Cancer Syndromes
Ho, T. H., & Jonasch, E. W. (2014) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2014.0129 · Cited by 25
Targeting succinate:ubiquinone reductase potentiates the efficacy of anticancer therapy
Kruspig, B., Valter, K., Skender, B., Zhivotovsky, B., & Gogvadze, V. G. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.04.026 · Cited by 27
Succinate dehydrogenase deficiency in a PDGFRA mutated GIST
Belinsky, M. G., Cai, K. Q., Zhou, Y., et al. (2017) · BMC Cancer · doi:10.1186/s12885-017-3499-7 · Cited by 26
“These enzymes include the prolyl hydroxylase (PHD) that normally contributes to the degradation of the hypoxia-inducible gactor-1A (HIF1A) [48] as well as TET family DNA hydroxylases that are required for demethylation of genomic DNA [49].”
BackgroundLi, X., An, J., Li, H., Qiu, X., Wei, Y., & Shang, Y. (2019) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2019.109391 · Cited by 26
Heat-shock protein 90 inhibitors in antineoplastic therapy: is it all wrapped up?
Isaacs, J. S. (2005) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.14.6.569 · Cited by 26
“In a second example, the authors and others have recently reported that intermediates from the Krebs cycle, the accumulation of which is associated with a subset of hereditary cancer syndromes, inhibit HPH function by competing with a cosubstrate of the enzyme (Isaacs, unpublished data) [75].”
BackgroundFrom Gasotransmitter to Immunomodulator: The Emerging Role of Hydrogen Sulfide in Macrophage Biology
Cornwell, A., & Badiei, A. (2023) · Antioxidants · doi:10.3390/antiox12040935 · Cited by 27
“During inflammation, the accumulation of succinate in the cytosol, due to its transport from the mitochondria, can lead to the inhibition of prolyl hydroxylase activity and the stabilization of hypoxia inducible factor (HIF)-1α [89,90].”
BackgroundLiu, K., Zhou, Y., Song, X., Zeng, J., Wang, Z., Wang, Z., Zhang, H., Xu, J., Li, W., Gong, Z., et al. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155570 · Cited by 26
Redox imbalance and hypoxia‐inducible factors: a multifaceted crosstalk
Ravi, R., & Singh, J. (2025) · FEBS Journal · doi:10.1111/febs.70013 · Cited by 29
D’Alessandro, A., Nemkov, T. G., Moore, H. B., Moore, E. E., Wither, M. J., Nydam, T. L., Slaughter, A. L., Silliman, C. C., Banerjee, A. M., & Hansen, K. C. (2016) · PubMed Central · doi:10.2450/2016.0208-15 · Cited by 26
Metabolic Reprogramming of Mouse Bone Marrow Derived Macrophages Following Erythrophagocytosis
Catala, A., Youssef, L. A., Reisz, J. A., Dzieciątkowska, M., Powers, N. E., Marchetti, C., Karafin, M. S., Zimring, J. C., Hudson, K. E., Hansen, K. C., et al. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00396 · Cited by 28
“Succinate can then stabilize hypoxia-inducible factor 1-alpha (HIF-1α) via inhibited hydroxylation, inducing expression of glycolytic enzymes and proinflammatory IL-1β (Tannahill et al., 2013).”
BackgroundSuccinate dehydrogenase and MYC-associated factor X mutations in pituitary neuroendocrine tumours
Loughrey, P. B., Roncaroli, F., Healy, E. G., Weir, P., Madhu, B., Casey, R. T., Hunter, S. J., & Korbonits, M. (2022) · Endocrine Related Cancer · doi:10.1530/erc-22-0157 · Cited by 28
Li, X., Li, Y., Liu, B., Chen, L., Lyu, F., Zhang, P., He, Q., Cheng, L., Liu, C., Song, Y., et al. (2023) · The FASEB Journal · doi:10.1096/fj.202201247r · Cited by 27
Targeting the Metabolic Paradigms in Cancer and Diabetes
Bosso, M., Haddad, D., Madhoun, A. S. A., & Al‐Mulla, F. (2024) · Biomedicines · doi:10.3390/biomedicines12010211 · Cited by 26
“In addition to its role in cancer, it plays a role in glucose metabolism and insulin sensitivity [107,402].”
BackgroundHigh-Throughput Screening for Growth Inhibitors Using a Yeast Model of Familial Paraganglioma
Bancos, I., Bida, J. P., Tian, D., Bundrick, M., John, K., Holte, M. N., Her, Y. F., Evans, D. L., Saenz, D. T., Poeschla, E. M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056827 · Cited by 25
“According to the Su accumulation hypothesis [18,23,26,28,29], SDH mutations inactivate SDH activity and Su accumulates in the cell (Fig.”
BackgroundSpégel, P., Andersson, L. E., Storm, P., Sharoyko, V. V., Göhring, I., Rosengren, A. H., & Mulder, H. (2015) · Endocrinology · doi:10.1210/en.2014-1391 · Cited by 25
“inducible factors (HIFs) (45); HIF1 has experimentally”
Naranjo‐Suarez, S., Carlson, B. A., Tobe, R., Yoo, M., Tsuji, P. A., Gladyshev, V. N., & Hatfield, D. L. (2013) · Molecules and Cells · doi:10.1007/s10059-013-0121-y · Cited by 25
Akhtar, M. Z., Huang, H., Kaisar, M. O., Faro, M. L. L., Rebolledo, R. A., Morten, K., Heather, L. C., Dona, A. C., Leuvenink, H. G. D., Fuggle, S., et al. (2015) · American Journal of Transplantation · doi:10.1111/ajt.13626 · Cited by 24
Cancer metabolism in a snapshot: MRS(I)
Julià‐Sapé, M., Candiota, A. P., & Arús, C. (2019) · NMR in Biomedicine · doi:10.1002/nbm.4054 · Cited by 25
Increased HIF1α in SDH and FH deficient tumors does not cause microsatellite instability
Lehtonen, H. J., Mäkinen, M. J., Kiuru, M. H., Laiho, P., Herva, R., van Minderhout, I. J. H. M., Hogendoorn, P. C. W., Cornelisse, C. J., Devilee, P., Launonen, V., et al. (2007) · International Journal of Cancer · doi:10.1002/ijc.22819 · Cited by 26
Longitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer
Wang, K., Zerdes, I., Johansson, H. J., Sarhan, D., Sun, Y., Kanellis, D. C., Sifakis, E. G., Mezheyeuski, A., Liu, X., Loman, N., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47932-y · Cited by 22
Decoding mitochondria's role in immunity and cancer therapy
Zhang, Y., YAN, H. H., Wei, Y., & Wei, X. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189107 · Cited by 30
Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK
Peng, C., Jiang, H., Jing, L., Yang, W., Guan, X., Wang, H., Yu, S., Cao, Y., Wang, M., Ma, H., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57044-w · Cited by 26
Wang, X., & Xiong, X. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s510972 · Cited by 28
Canonical and new generation anticancer drugs also target energy metabolism
Rodríguez‐Enríquez, S., Gallardo‐Pérez, J. C., Hernández‐Reséndiz, I., Marín‐Hernández, Á., Pacheco-Velázquez, S. C., López‐Ramírez, S. Y., Rumjanek, F. D., & Moreno‐Sánchez, R. (2014) · Archives of Toxicology · doi:10.1007/s00204-014-1246-2 · Cited by 24
“The mutant enzymes become inactive promoting the accumulation of succinate and fumarate (Isaacs et al. 2005; Pollard et al. 2005; Selak et al. 2005).”
BackgroundMetabolic, autophagic, and mitophagic activities in cancer initiation and progression
Hjelmeland, A. B., & Zhang, J. (2016) · Biomedical Journal · doi:10.1016/j.bj.2015.10.002 · Cited by 24
“[106] Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, et al.”
BackgroundThe von Hippel–Lindau Tumor Suppressor Protein
Kaelin, W. G. (2018) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030617-050527 · Cited by 24
“The inactivation of SDH and FH causes the accumulation of succinate and fumarate, which inhibit various 2-oxoglutaratedependent dioxygenases, including the EGLNs (Isaacs et al. 2005, Lu et al. 2005, Selak et al. 2005).”
Metabolic memory underlying minimal residual disease in breast cancer
Shechter, K. R., Kafkia, E., Zirngibl, K., Gawrzak, S., Alladin, A., Machado, D., Lüchtenborg, C., Sévin, D. C., Brügger, B., Patil, K. R., et al. (2021) · Molecular Systems Biology · doi:10.15252/msb.202010141 · Cited by 25
“Next, an empirical Bayes moderated t-statistic and log-odds were computed with the “eBayes” function of the limma package version 3.38.3 (Smyth, 2004; Ritchie et al, 2015) using the package defaults.”
MethodInfluentialWang, X., Xu, B., Du, J., Xia, J., Lei, G., Zhou, C., Hu, J., Zhang, Y., Chen, S., Shao, F., et al. (2022) · Cancer Cell International · doi:10.1186/s12935-022-02739-z · Cited by 25
Intersections between mitochondrial sirtuin signaling and tumor cell metabolism
Herrera, K. N. G., Lee, J. J., & Haigis, M. C. (2015) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2015.1031879 · Cited by 25
“In the presence of oxygen, HIF1a is hydroxylated by prolyl hydroxylases (PHD), a family of dioxygenases, activated by a-ketoglutarate and inhibited by succinate (Kaelin & Thompson, 2010; Selak et al., 2005).”
Holotnakova, T., Ziegelhöffer, A., Ohradanova‐Repic, A., Hulı́ková, A., Novàkovâ, M., Kopáček, J., Pastorek, J., & Pastoreková, S. (2007) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-007-0400-6 · Cited by 24
“tosis, and renal cancer syndrome that result from inactivation of two tumor suppressor genes, namely succinate dehydrogenase (SDH) and fumarate hydratase, respectively [7, 34, 28, 29, 20].”
BackgroundHypoxia in the intestine or solid tumors: A beneficial or deleterious alarm signal?
Shehade, H., Oldenhove, G., & Moser, M. (2014) · European Journal of Immunology · doi:10.1002/eji.201444719 · Cited by 26
Mitochondrial bioenergetics and disease in Caenorhabditis elegans
Rabbitts, B. M. (2015) · Frontiers in bioscience · doi:10.2741/4305 · Cited by 26
“Moreover, the mitochondrion plays a crucial role in a wide array of diseases including cancer, type 2 diabetes, Huntington’s, Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis, and Freiderich’s ataxia (15,16,17,18).”
BackgroundKlawitter, J., Klawitter, J., Gurshtein, J., Corby, K., Fong, S., Tagliaferri, M. A., Quattrochi, L. C., Cohen, I. V., Shtivelman, E., & Christians, U. (2011) · International Journal of Cancer · doi:10.1002/ijc.25965 · Cited by 24
“mulation of succinate suppresses HIF-1a prolyl hydroxylases in the cytosol, while facilitating angiogenesis, metastasis and ultimately leading to tumor progression.(37) In our model, inhibition of the aforementioned enzymes kept the concentrations of succinate at low levels during Bezielle’s exposure.”
BackgroundRole of Oxygen in Cancer: Looking Beyond Hypoxia
López‐Lázaro, M. (2009) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/187152009788451806 · Cited by 24
Backman, S., Maharjan, R., Falk-Delgado, A., Crona, J., Cupisti, K., Stalberg, P. L. H., Hellman, P., & Björklund, P. (2017) · Scientific Reports · doi:10.1038/srep44943 · Cited by 23
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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