The DOI matches its Crossref record; 45 of the 47 references it cites were found in a registry or an index; 1 of the 7 sources its claims cite were checked for support.
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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Written from the paper’s full text.
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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Items 301–400 of 2,106
Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells
Cervera, A. M., Bayley, J.-P., Devilee, P., & McCreath, K. J. (2009) · Molecular Cancer · doi:10.1186/1476-4598-8-89 · Cited by 156
“Semi-quantitative PCR was then performed using specific oligonucleotide primers for SDHD [11] and cyclophilin [10].”
BackgroundMethodInfluentialHereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics
Lehtonen, H. J. (2011) · Familial Cancer · doi:10.1007/s10689-011-9428-z · Cited by 156
“ROS as a known HIF1 regulator has been suggested to act in parallel with excess succinate as an activator of HIF1 [75, 88].”
BackgroundMethodAMP kinase promotes glioblastoma bioenergetics and tumour growth
Chhipa, R. R., Fan, Q., Anderson, J., Muraleedharan, R., Huang, Y., Ciraolo, G. M., Chen, X., Waclaw, R. R., Chow, L. M. L., Khuchua, Z. A., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0126-z · Cited by 154
State of the Science: An Update on Renal Cell Carcinoma
Jonasch, E. W., Futreal, P. A., Davis, I. J., Bailey, S. T., Kim, W. Y., Brugarolas, J., Giaccia, A. J., Kurban, G., Pause, A., Frydman, J., et al. (2012) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-12-0117 · Cited by 165
“The accumulation of succinate or fumarate causes the inhibition of a family of 2-oxoglutarate-dependent dioxygeneases normally implicated in HIF-α hydroxylation [134-136].”
BackgroundItaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injury
Cordes, T., Lucas, A., Divakaruni, A. S., Murphy, A. N., Cabrales, P., & Metallo, C. M. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.11.019 · Cited by 156
Proteomic Analysis of Colorectal Cancer Reveals Alterations in Metabolic Pathways
Bi, X., Lin, Q., Foo, T. W. J., Joshi, S. B., You, T., Shen, H., Ong, C. N., Cheah, P. Y., Eu, K. W., & Hew, C. (2006) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m500432-mcp200 · Cited by 153
“The mitochondrial enzyme succinate dehydrogenase, which links tricarboxylic acid cycle dysfunction to oncogenesis via hypoxia-inducible factor (HIF)-1 was also demonstrated recently (18).”
BackgroundLee, J., Jo, D., Park, D., Chung, H. Y., & Mattson, M. P. (2014) · Pharmacological Reviews · doi:10.1124/pr.113.007757 · Cited by 155
“In addition to oxygen, the stability of HIF-1a is also regulated by metabolic status because the tricarboxylic acid cycle intermediate a-ketoglutarate is also a substrate for PHDs.”
BackgroundInfluentialGasparre, G., Hervouet, É., de Laplanche, E., Demont, J., Pennisi, L. F., Colombel, M. C., Mège‐Lechevallier, F., Scoazec, J., Bonora, E., Smeets, R., et al. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm371 · Cited by 154
“Intermediary metabolite levels could be involved in the signaling for cell growth as put forward by the works of Gottlieb and co-workers (41).”
BackgroundLee, S., & Griffiths, J. R. (2020) · Cancers · doi:10.3390/cancers12061616 · Cited by 163
Brière, J.-J., Favier, J., Bénit, P., Ghouzzi, V. E., Lorenzato, A., Rabier, D., Renzo, M. F. D., Gimenez‐Roqueplo, A., & Rustin, P. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi359 · Cited by 162
“proteasome-catalyzed HIF1a degradation) (9,10).”
BackgroundInfluentialRationale and Evidence for Sunitinib in the Treatment of Malignant Paraganglioma/Pheochromocytoma
Joshua, A. M., Ezzat, S., Asa, S. L., Evans, A. J., Broom, R. J., Freeman, M., & Knox, J. J. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1836 · Cited by 149
The Mitochondrial Complex(I)ty of Cancer
Urra, F. A., Muñoz, F., Lovy, A., & Cárdenas, C. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00118 · Cited by 149
“Upon Complex I inhibition, NADH accumulation allosterically inhibits the TCA cycle enzyme α-ketoglutarate (αKG) dehydrogenase, thereby increasing the α-ketoglutarate/succinate (αKG/Suc) ratio, which favors the activity of the prolyl-hydroxylases in charge of the degradation of HIF1α, and causing tumor growth arrest (1…”
BackgroundMuller, F. L., Liu, Y., Abdul-Ghani, M. A., Lustgarten, M. S., Bhattacharya, A., Jang, Y. C., & Van Remmen, H. (2008) · Biochemical Journal · doi:10.1042/bj20071162 · Cited by 150
Oncometabolites‐driven tumorigenesis: From genetics to targeted therapy
Morin, A., Letouzé, É., Gimenez‐Roqueplo, A., & Favier, J. (2014) · International Journal of Cancer · doi:10.1002/ijc.29080 · Cited by 162
“In SDH-deficient cells, the massive cytoplasmic excess in succinate acts as a competitive inhibitor of PHDs thereby promoting inappropriate stabilization and activation of HIF-1a and HIF-2a.27,28 Table 1.”
BackgroundKrebs cycle rewired for macrophage and dendritic cell effector functions
Ryan, D. G., & O'Neill, L. A. J. (2017) · FEBS Letters · doi:10.1002/1873-3468.12744 · Cited by 154
Dysregulation of the TET family of epigenetic regulators in lymphoid and myeloid malignancies
Lio, C. J., Yuita, H., & Rao, A. (2019) · Blood · doi:10.1182/blood.2019791475 · Cited by 152
HIF in the heart: development, metabolism, ischemia, and atherosclerosis
Knutson, A. K., Williams, A. L., Boisvert, W. A., & Shohet, R. V. (2021) · Journal of Clinical Investigation · doi:10.1172/jci137557 · Cited by 158
“Given the reduced ATP production of glycolysis compared with oxidative phosphorylation, long-term HIF1 stabilization may not always be beneficial, as observed in heart failure Work in cancer cells shows that several additional citric acid and glycolytic metabolites can also regulate PHD activity and HIF stability (84,…”
BackgroundMetabolic reprogramming, sensing, and cancer therapy
Mao, Y., Xia, Z., Xia, W., & Jiang, P. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.115064 · Cited by 180
Yang, C., Zhuang, Z., Fliedner, S. M. J., Shankavaram, U. T., Sun, M. G., Bullova, P., Zhu, R., ELKAHLOUN, A. G., Kourlas, P. J., Merino, M. J., et al. (2014) · Journal of Molecular Medicine · doi:10.1007/s00109-014-1205-7 · Cited by 153
“High succinate levels inhibit PHD activity [25].”
Inborn and acquired metabolic defects in cancer
Frezza, C., Pollard, P. J., & Gottlieb, E. (2011) · Journal of Molecular Medicine · doi:10.1007/s00109-011-0728-4 · Cited by 147
“The molecular link between TCA cycle dysfunction and HIF activation was initially proposed by Selak and colleagues who demonstrated that the accumulation of succinate in SDH-deficient cells causes the inhibition of the HIF prolyl 4-hydroxylases (PHDs), important regulators of the stability of the α subunit of HIF [33].”
BackgroundSelf-citationThe metabolic basis of kidney cancer
Linehan, W. M., & Ricketts, C. J. (2012) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2012.06.002 · Cited by 152
The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells
Prochownik, E. V., & Wang, H. (2021) · Cells · doi:10.3390/cells10040762 · Cited by 150
Emerging novel functions of the oxygen-sensing prolyl hydroxylase domain enzymes
Wong, B. W., Kuchnio, A., Brüning, U., & Carmeliet, P. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.10.004 · Cited by 144
Zacharias, N. M., Chan, H. R., Sailasuta, N., Ross, B. D., & Bhattacharya, P. K. (2011) · Journal of the American Chemical Society · doi:10.1021/ja2040865 · Cited by 144
Chinopoulos, C. (2013) · Journal of Neuroscience Research · doi:10.1002/jnr.23196 · Cited by 148
“Succinate exits mitochondria and will inhibit HIF-a prolyl hydroxylase, thereby stabilizing and activating HIF-1a, initiating a hypoxic response (Selak et al., 2005; Semenza, 2007); this phenomenon is extremely important in tumorigenesis (Raimundo et al., 2011).”
BackgroundRodríguez-Enríquez, S., Carreño-Fuentes, L., Gallardo-Pérez, J. C., Saavedra, E., Quezada, H., Vega, A., Marín-Hernández, A., Olín-Sandoval, V., Torres-Márquez, M. E., & Moreno-Sánchez, R. (2010) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2010.07.010 · Cited by 142
Oncometabolites: tailoring our genes
Nowicki, S., & Gottlieb, E. (2015) · FEBS Journal · doi:10.1111/febs.13295 · Cited by 148
Self-citationCell-permeable succinate prodrugs bypass mitochondrial complex I deficiency
Ehinger, J. K., Piel, S., Ford, R., Karlsson, M., Sjövall, F., Frostner, E. Å., Morota, S., Taylor, R. W., Turnbull, D. M., Cornell, C. L., et al. (2016) · Nature Communications · doi:10.1038/ncomms12317 · Cited by 144
Physiology of the Carotid Body: From Molecules to Disease
Ortega‐Sáenz, P., & López‐Barneo, J. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020518-114427 · Cited by 143
“Mutations in the succinate dehydrogenase subunit D (SDHD) are the most common cause of hereditary CB paraganglioma (149), and it has been suggested that succinate accumulation, PHD inhibition, and HIF stabilization could be critical events triggering the appearance of paragangliomas (150, 151).”
BackgroundPhaeochromocytoma, new genes and screening strategies
Gimenez‐Roqueplo, A., Lehnert, H., Mannelli, M., Neumann, H., Opocher, G., Maher, E. R., Plouin, P., & on behalf of the European Network for the Study of Adrenal Tumours (ENS@T) Pheochromocytoma Working Group (2006) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2006.02714.x · Cited by 141
Morandi, A., Taddei, M. L., Chiarugi, P., & Giannoni, E. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00040 · Cited by 146
“These environmental inputs drive the expression and stabilization of the hypoxia-inducible factor-1α (HIF-1α).”
BackgroundInfluentialAcute Iron Deprivation Reprograms Human Macrophage Metabolism and Reduces Inflammation In Vivo
Pereira, M., Chen, T., Buang, N. B., Olona, A., Ko, J., Prendecki, M. F., Costa, A. S. H., Nikitopoulou, E., Tronci, L., Pusey, C. D., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.039 · Cited by 140
“We observed a macrophage pseudohypoxia transcriptome (i.e., HIF response in the presence of oxygen; Selak et al., 2005; Tannahill et al., 2013) with DEF treatment, which was previously described in LPS-stimulated macrophages (Tannahill et al., 2013).”
BackgroundTranslational control of gene expression during hypoxia
van den Beucken, T., Koritzinsky, M., & Wouters, B. G. (2006) · Cancer Biology & Therapy · doi:10.4161/cbt.5.7.2972 · Cited by 145
Salminen, A., Kauppinen, A., Hiltunen, M. O., & Kaarniranta, K. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.05.004 · Cited by 145
Regulation of angiogenesis by oxygen sensing mechanisms
Fong, G. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0458-z · Cited by 143
Pollard, P. J., El-Bahrawy, M. A., Poulsom, R., Elia, G., Killick, P., Kelly, G. P., Hunt, T., Jeffery, R. E., Seedhar, P., Barwell, J., et al. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-0920 · Cited by 140
The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells
Masgras, I., Sànchez‐Martìn, C., Colombo, G., & Rasola, A. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00058 · Cited by 143
“Indeed, TRAP1-dependent inhibition of SDH leads to the consequent increase in intracellular succinate levels, which in turn stabilizes the transcription factor HIF1α, as already postulated (67).”
BackgroundMetabolic features of cancer stem cells: the emerging role of lipid metabolism
Mancini, R., Noto, A., Pisanu, M. E., Vitis, C. D., Maugeri‐Saccà, M., & Ciliberto, G. (2018) · Oncogene · doi:10.1038/s41388-018-0141-3 · Cited by 140
Effects of hypoxia on tumor metabolism
Kim, J., Gao, P., & Dang, C. V. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9060-4 · Cited by 146
HIF-independent role of prolyl hydroxylases in the cellular response to amino acids
Durán, R. V., MacKenzie, E. D., Boulahbel, H., Frezza, C., Heiserich, L., Tardito, S., Bussolati, O., Rocha, S., Hall, M. N., & Gottlieb, E. (2013) · Oncogene · doi:10.1038/onc.2012.465 · Cited by 139
Self-citationLi, Y., Liu, Y., Wang, C., Xia, W., Zheng, J., Yang, J. W., Liu, B., Liu, J., & Liu, L. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.07.009 · Cited by 146
A break in mitochondrial endosymbiosis as a basis for inflammatory diseases
Murphy, M. P., & O’Neill, L. A. J. (2024) · Nature · doi:10.1038/s41586-023-06866-z · Cited by 138
“Mitochondrial metabolites such as succinate and α-ketoglutarate can also alter DNA and histone methylation as potential epigenetic signals 87–89 .”
Novel Genetic Causes of Pituitary Adenomas
Caimari, F., & Korbonits, M. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0452 · Cited by 137
Buffet, A., Morin, A., Castro‐Vega, L. J., Habarou, F., Lussey‐Lepoutre, C., Letouzé, É., Lefèbvre, H., Guilhem, I., Haissaguerre, M., Raingeard, I., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-2463 · Cited by 137
Cancer metabolism and tumor microenvironment: fostering each other?
Yuan, Y., Li, H., Wang, P., Chen, L., Guo, D. S., Jiang, H., He, B., Qin, S., Wang, K., Li, N., et al. (2021) · Science China Life Sciences · doi:10.1007/s11427-021-1999-2 · Cited by 140
“…and fumarate in SDH or FH tumor cells results in inhibition of α-KG-dependent prolyl hydroxylases (PHDs) and, therefore, the accumulation of HIF1α, a transcription factor whose stabilization and elevation could promote cell metabolism and angiogenesis (Isaacs et al., 2005; Selak et al., 2005).”
BackgroundNonezymatic formation of succinate in mitochondria under oxidative stress
Fedotcheva, N. I., Sokolov, A. P., & Kondrashova, M. N. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.02.012 · Cited by 141
Lactic Acidosis Triggers Starvation Response with Paradoxical Induction of TXNIP through MondoA
Chen, J. L.-Y., Merl, D., Peterson, C. W., Wu, J., Liu, P. Y., Yin, H., Muoio, D. M., Ayer, D. E., West, M., & Chi, J. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001093 · Cited by 136
Hypoxia-Inducible Factor-1: A Critical Player in the Survival Strategy of Stressed Cells
Chen, S., & Sang, N. (2015) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25283 · Cited by 137
“Mutations of succinate dehydrogenase (SDH) and fumarate hydratase (FH), two enzymes of the tricarboxylic acid cycle, were found to block PHDs activity and increase HIF-1a protein levels by increasing the concentration of succinate and fumarate respectively, which act as PHD inhibitors [Isaacs et al., 2005; Pollard et…”
BackgroundAltered metabolism and mitochondrial genome in prostate cancer
Dakubo, G. D., Parr, R. L., Costello, L. C., FRANKLIN, R. B., & Thayer, R. E. (2006) · Journal of Clinical Pathology · doi:10.1136/jcp.2005.027664 · Cited by 135
Ralph, S. J., Moreno-Sánchez, R., Neuzil, J., & Rodríguez-Enríquez, S. (2011) · Pharmaceutical Research · doi:10.1007/s11095-011-0566-7 · Cited by 126
Richter, S., Peitzsch, M., Rapizzi, E., Lenders, J. W., Qin, N., de Cubas, A. A., Schiavi, F., Rao, J. U., Beuschlein, F., Quinkler, M., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2151 · Cited by 135
The role of complex II in disease
Hoekstra, A. S., & Bayley, J. (2012) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2012.11.005 · Cited by 145
“We still do not know if the primary link between loss of complex II and tumorigenesis is due to the activation of HIF1 through the accumulation of succinate [86,87], due to the generation of ROS [3] or to other mechanisms such as inhibition of histone demethylases [88] or inhibition of EglN3-mediated apoptosis [89].”
BackgroundMitochondrial metabolites: undercover signalling molecules
Frezza, C. (2017) · Interface Focus · doi:10.1098/rsfs.2016.0100 · Cited by 136
Oncometabolites lactate and succinate drive pro-angiogenic macrophage response in tumors
Kes, M. M. G., den Bossche, J. V., Griffioen, A. W., & Huijbers, E. J. M. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188427 · Cited by 138
In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas
Toledo, R. A., Qin, Y., Srikantan, S., Morales, N. P., Li, Q., Deng, Y., Kim, S.-W., Pereira, M. A. A., Toledo, S. P. A., Su, X., et al. (2013) · Endocrine Related Cancer · doi:10.1530/erc-13-0101 · Cited by 136
“The activity of PHDs is regulated in part by the abundance of the SDH substrate, succinate, which accumulates when SDH is deficient (Selak et al. 2005).”
BackgroundMitochondrial DNA Instability and Metabolic Shift in Human Cancers
Lee, H., & Wei, Y. (2009) · International Journal of Molecular Sciences · doi:10.3390/ijms10020674 · Cited by 134
“Thus, succinate can increase the expression of genes that facilitate glycolysis in cancer cells [134,135].”
BackgroundClinical aspects of SDHx-related pheochromocytoma and paraganglioma
Timmers, H. J. L. M., Gimenez‐Roqueplo, A., Mannelli, M., & Pacák, K. (2009) · Endocrine Related Cancer · doi:10.1677/erc-08-0284 · Cited by 131
Magar, A. G., Morya, V. K., Kwak, M. K., Oh, J. U., & Noh, K.-C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063313 · Cited by 150
“The higher expression of IDH-3 α mediates HIF-1 α -induced metabolic reprogramming and angiogenesis [58,59].”
BackgroundMetabolic alterations in cancer cells and therapeutic implications
Hammoudi, N., Ahmed, K. B. R., Garcı́a-Prieto, C., & Huang, P. (2011) · 癌症：英文版 · doi:10.5732/cjc.011.10267 · Cited by 137
Tseng, C.-W., Kuo, W., Chan, S., Chan, H., Chang, K., & Wang, L. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-2906 · Cited by 131
Chinopoulos, C., & Seyfried, T. N. (2018) · ASN NEURO · doi:10.1177/1759091418818261 · Cited by 130
“In this sense, succinate has been considered a proinflammatory oncometabolite (Selak et al., 2005; Tannahill et al., 2013; Tretter et al., 2016).”
BackgroundDysregulation of metabolic pathways in pulmonary fibrosis
Rajesh, R., Atallah, R., & Bärnthaler, T. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108436 · Cited by 132
Oxidative metabolism in cancer growth
Ristow, M. (2006) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/01.mco.0000232892.43921.98 · Cited by 132
18F-FDG Avidity of Pheochromocytomas and Paragangliomas: A New Molecular Imaging Signature?
Taïeb, D., Sebag, F. A., Barlier, A., Tessonnier, L., Palazzo, F. F., Morange, I., Niccoli, P., Fakhry, N., Micco, C. D., Cammilleri, S., et al. (2009) · Journal of Nuclear Medicine · doi:10.2967/jnumed.108.060731 · Cited by 129
The bioenergetics of cancer: Is glycolysis the main ATP supplier in all tumor cells?
Moreno‐Sánchez, R., Rodríguez‐Enríquez, S., Saavedra, E., Marín‐Hernández, Á., & Gallardo‐Pérez, J. C. (2009) · BioFactors · doi:10.1002/biof.31 · Cited by 134
“Low expression and activity of OxPhos enzymes and transporters Krebs cycle enzymes Transformed mesenchymal cells, phaeochromocytomas, paragangliomas, liomyomas, leiomyosarcomas, renal cell, gastric and colon carcinomas, and papillary thyroid cancer [2,18,21–24]”
BackgroundAlston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig‐Do, H., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., et al. (2012) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2012-101146 · Cited by 135
The α-ketoglutarate dehydrogenase complex in cancer metabolic plasticity
Vatrinet, R., Leone, G., Luise, M. D., Girolimetti, G., Vidone, M., Gasparre, G., & Porcelli, A. M. (2017) · Cancer & Metabolism · doi:10.1186/s40170-017-0165-0 · Cited by 133
Huang, H., Li, G., He, Y., Chen, J., Yan, J., Zhang, Q., Li, L., & Cai, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1404441 · Cited by 155
“Although this activation is bene fi cial for cellular adaptation to hypoxic conditions, excessive succinate can induce a “ pseudohypoxia ” state (41, 42), enhancing HIF-1 a activity even in oxygen-rich environments, a condition frequently observed in tumors with mutated SDH (43).”
BackgroundHepatic response to aluminum toxicity: Dyslipidemia and liver diseases
Mailloux, R. J., Lemire, J., & Appanna, V. D. (2011) · Experimental Cell Research · doi:10.1016/j.yexcr.2011.07.009 · Cited by 131
“[37] M.”
BackgroundMitochondrial oxidative phosphorylation TRAP(1)ped in tumor cells
Rasola, A., Neckers, L., & Picard, D. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.03.005 · Cited by 129
Isocitrate Dehydrogenase Mutations Are Rare in Pheochromocytomas and Paragangliomas
Gaal, J., Burnichon, N., Korpershoek, E., Roncelin, I., Bertherat, J. Y., Plouin, P., de Krijger, R. R., Gimenez‐Roqueplo, A., & Dinjens, W. N. M. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2170 · Cited by 131
Zhang, J., Yao, M., Xia, S., Zeng, F., & Liu, Q. (2025) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-024-00682-7 · Cited by 150
Pharmacological targeting of the HIF hydroxylases – A new field in medicine development
Chan, M. C., Holt‐Martyn, J. P., Schofield, C. J., & Ratcliffe, P. J. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.01.001 · Cited by 128
Isocitrate dehydrogenases in physiology and cancer: biochemical and molecular insight
Al‐Khallaf, H. (2017) · Cell & Bioscience · doi:10.1186/s13578-017-0165-3 · Cited by 133
“It is thought that succinate accumulation inhibits, prolyl hydroxylase (PHD), a 2KG-utilizing enzyme, due to the structural similarity between them [45].”
BackgroundO'Kane, G. M., Ezzat, S., Joshua, A. M., Bourdeau, I., Leibowitz‐Amit, R., Olney, H. J., Krzyzanowska, M. K., Reuther, D., Chin, S. F., Wang, L. E., et al. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0474-x · Cited by 126
Mitochondria-controlled signaling mechanisms of brain protection in hypoxia
Lukyanova, L. D., & Kirova, Y. I. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00320 · Cited by 126
“However it recovered in the presence of succinate (Vaux et al., 2001; Paddenberg et al., 2003; Napolitano et al., 2004; Selak et al., 2005; Hewitson et al., 2007; Koivunen et al., 2007).”
BackgroundFunctional polarization of tumor-associated macrophages dictated by metabolic reprogramming
Zeng, W., Li, F., Jin, S., Ho, P., Liu, P.-S., & Xie, X. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02832-9 · Cited by 139
“Accelerated glycolysis results in the accumulation of succinate in TCA cycle, and elevated succinate levels inhibit PHD due to the competitive binding to its active site [80].”
BackgroundMu, X., Zhao, T., Xu, C., Shi, W., Geng, B., Shen, J., Zhang, C., Pan, J., Yang, J., Hu, S., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.14485 · Cited by 124
“For example, succinate accumulates in succinate dehydrogenase-deficient tumors like gastrointestinal stromal tumors (GIST), inhibits prolyl hydroxylase activity with subsequent HIF-1α stabilization and therefore drives cancer progression [11, 12].”
BackgroundKarakelides, H., Asmann, Y. W., Bigelow, M. L., Short, K. R., Dhatariya, K., Coenen-Schimke, J., Kahl, J., Mukhopadhyay, D., & Nair, K. S. (2007) · Diabetes · doi:10.2337/db07-0378 · Cited by 123
SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery
Saxena, N., Maio, N., Crooks, D. R., Ricketts, C. J., Yang, Y., Wei, M.-H., Fan, T. W. ‐., Lane, A. N., Sourbier, C., Singh, A., et al. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djv287 · Cited by 125
“sible for targeting hypoxia inducible factors HIF1α and HIF2α for degradation (15).”
BackgroundMitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?
Lemarié, A., & Grimm, S. (2011) · Oncogene · doi:10.1038/onc.2011.167 · Cited by 126
“Consequences on oxidative stress SDHD siRNA/shRNA (transient 30–48 h) DHE (superoxides) (microscopy) Absence of ROS detection (Selak et al., 2005) (Selak et al.”
BackgroundReactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death
Tennant, D. A., Frezza, C., MacKenzie, E. D., Nguyen, Q., Zheng, L., Selak, M. A., Roberts, D. L., Dive, C., Watson, D. G., Aboagye, E. O., et al. (2009) · Oncogene · doi:10.1038/onc.2009.250 · Cited by 122
“We and others have previously demonstrated that in cells with a deficiency in the enzyme succinate dehydrogenase (SDH) increased levels of succinate competitively inhibit PHDs even in the presence of oxygen, resulting in a pseudohypoxic phenotype characterized by HIF induction (Lee et al., 2005; Selak et al., 2005).”
BackgroundMethodSelf-citationFarrugia, F., & Charalampopoulos, A. A. (2019) · Endocrine Regulations · doi:10.2478/enr-2019-0020 · Cited by 123
“HIFs contribute to the pathogenesis of various diseases.”
BackgroundInfluentialThe genetic and metabolic signature of oncocytic transformation implicates HIF1α destabilization
Porcelli, A. M., Ghelli, A. M., Ceccarelli, C., Lang, M., Cenacchi, G., Capristo, M., Pennisi, L. F., Morra, I., CICCARELLI, E., Melcarne, A., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp566 · Cited by 121
Cellular metabolism of myeloid cells in sepsis
Arts, R. J. W., Gresnigt, M. S., Joosten, L. A. B., & Netea, M. G. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.4mr0216-066r · Cited by 126
“In contrast, the TCA cycle metabolite a-ketoglutarate can inhibit Hif1a and IL-1b induction [27, 61, 62].”
BackgroundMatias, M. I., Yong, C. S. M., Foroushani, A. B. K., Goldsmith, C., Mongellaz, C., Sezgin, E., Levental, K. R., Talebi, A., Perrault, J., Riviere, A., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109911 · Cited by 124
“8 Cell Reports 37, 109911, November 2, 2021 nificant, succinate has both cytosolic and mitochondrial effects (King et al., 2006; Koivunen et al., 2007; Selak et al., 2005).”
BackgroundDevelopment of novel therapeutic strategies that target HIF-1
Semenza, G. L. (2006) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.10.2.267 · Cited by 120
“The second mechanism involves loss of function for succinate dehydrogenase (SDH) or fumarate hydratase (FH), two enzymes of the Krebs (tricarboxylic acid) cycle [41,42].”
BackgroundSiddiq, A., Aminova, L. R., & Ratan, R. R. (2007) · Neurochemical Research · doi:10.1007/s11064-006-9268-7 · Cited by 121
“There are contradictory reports regarding the effects of other TCA cycle metabolites such as fumarate and succinate on HIF-1 activation [59,73-75].”
BackgroundProlyl 4‐hydroxylases, master regulators of the hypoxia response
Myllyharju, J. (2013) · Acta Physiologica · doi:10.1111/apha.12096 · Cited by 123
“2OG is generated in the citric acid cycle, and fumarate and succinate, other intermediates of this cycle, have been shown to inhibit HIF-P4Hs (Isaacs et al. 2005, Lu et al. 2005, Selak et al. 2005, Hewitson et al. 2007, Koivunen et al. 2007a).”
BackgroundMitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage
Cao, K., Riley, J. S., Heilig, R., Montes-Gómez, A. E., Vringer, E., Berthenet, K., Cloix, C., Elmasry, Y., Spiller, D. G., Ichim, G., et al. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.03.019 · Cited by 124
“For instance, mitochondrial respiratory complex proteins and TCA enzymes bearing tumor associated mutations generate oncometabolites (Isaacs et al., 2005; Pollard et al., 2007; Sciacovelli et al., 2016; Selak et al., 2005).”
Alterations of metabolic genes and metabolites in cancer
Oermann, E. K., Wu, J., Guan, K., & Xiong, Y. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.01.013 · Cited by 125
“Similarly, fumarate, the substrate of FH which is accumulated in FH-deficient cells, was also found to inhibit PHD leading to elevated levels of HIF-1α and HIF-2α proteins [72].”
BackgroundMitochondrial dysfunction in cancer: Potential roles of ATF5 and the mitochondrial UPR
Deng, P., & Haynes, C. M. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.05.002 · Cited by 121
Hypoxia, drug therapy and toxicity
Lee, K., Roth, R. A., & LaPres, J. J. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.08.001 · Cited by 118
Bayley, J., & Devilee, P. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.02.008 · Cited by 119
Succinate: An initiator in tumorigenesis and progression
Zhao, T., Mu, X., & You, Q. (2017) · Oncotarget · doi:10.18632/oncotarget.17734 · Cited by 118
“Elevated concentrations of succinate in the cytosol have been confirmed to inhibit HIF-1α prolyl hydroxylases (PHD) [20], which hereafter hydroxylate the highly conserved prolyl residues on HIF-1α.”
BackgroundInfluentialAutophagy paradox and ceramide
Jiang, W., & Öğretmen, B. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2013.09.005 · Cited by 123
Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells
Wenger, R. H., & Hoogewijs, D. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00736.2009 · Cited by 120
Genetic alterations in Krebs cycle and its impact on cancer pathogenesis
Sajnani, K., Islam, F., Smith, R. A., Gopalan, V., & Lam, A. K.-Y. (2017) · Biochimie · doi:10.1016/j.biochi.2017.02.008 · Cited by 121
Metabolomic Profiling of Drug Responses in Acute Myeloid Leukaemia Cell Lines
Tiziani, S., Lodi, A., Khanim, F. L., Viant, M. R., Bunce, C. M., & Günther, U. L. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004251 · Cited by 116
JmjC enzyme KDM2A is a regulator of rRNA transcription in response to starvation
Tanaka, Y., Okamoto, K., Teye, K., Umata, T., Yamagiwa, N., Suto, Y., Zhang, Y., & Tsuneoka, M. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.56 · Cited by 118
“PHD is an a-KG-dependent enzyme that catalyses a-KG to succinate during its hydroxylation reaction; in turn, the accumulated succinate inhibits PHD activity even under normoxia, which results in pseudohypoxia (Isaacs et al, 2005; Pollard et al, 2005; Selak et al, 2005).”
Background
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
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