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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
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Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer
Dussold, C., Zilinger, K., Turunen, J. R., Heimberger, A. B., & Miska, J. M. (2024) · Journal of Clinical Investigation · doi:10.1172/jci175445 · Cited by 81
Southam, A. D., Easton, J. M., Stentiford, G. D., Ludwig, C., Arvanitis, T. N., & Viant, M. R. (2008) · Journal of Proteome Research · doi:10.1021/pr800353t · Cited by 75
Zhang, Z., Yan, J., & Shi, H. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.07.012 · Cited by 72
Alternative assembly of respiratory complex II connects energy stress to metabolic checkpoints
Bezawork‐Geleta, A., Wen, H., Dong, L., Yan, B., Vider, J., Boukalová, Š., Krobova, L., Vanova, K. H., Zobalová, R., Sobol, M. A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04603-z · Cited by 73
Mitochondrial dependency in progression of acute myeloid leukemia
Basak, N. P., & Banerjee, S. (2015) · Mitochondrion · doi:10.1016/j.mito.2015.01.006 · Cited by 75
Ashrafian, H., O′Flaherty, L., Adam, J., Steeples, V., Chung, Y., East, P., Vanharanta, S., Lehtonen, H. J., Nye, E. L., Hatipoglu, E., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1949 · Cited by 72
Mitochondria in cancer metabolism, an organelle whose time has come?
Anderson, R. G., Ghiraldeli, L. P., & Pardee, T. S. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.05.005 · Cited by 76
Banerjee, S., Ghosh, S., Mandal, A., Ghosh, N., & Sil, P. C. (2020) · Archives of Toxicology · doi:10.1007/s00204-020-02801-7 · Cited by 74
“This HIF-1α enhances the transcription of IL-1β (Selak et al. 2005; Tannahill et al. 2013).”
BackgroundPhaeochromocytoma: a catecholamine and oxidative stress disorder
Pacák, K. (2011) · Endocrine Regulations · doi:10.4149/endo_2011_02_65 · Cited by 73
Histone Deacetylase Inhibitors: The Epigenetic Therapeutics That Repress Hypoxia‐Inducible Factors
Chen, S., & Sang, N. (2010) · BioMed Research International · doi:10.1155/2011/197946 · Cited by 73
Metabolic Mechanisms of Epigenetic Regulation
Meier, J. L. (2013) · ACS Chemical Biology · doi:10.1021/cb400689r · Cited by 75
Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice
Zou, X., Meng, J., Li, L., Han, W., Li, C., Zhong, R., Miao, X., Cai, J. C., Zhang, Y., & Zhu, D. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.676510 · Cited by 70
“demonstrated that increases in the levels of these oncometabolites play causal roles in tumorigenesis (26-34).”
BackgroundOvercoming the Warburg Effect: Is it the key to survival in sepsis?
Bar‐Or, D., Carrick, M. M., Tanner, A. H., Lieser, M. J., Rael, L. T., & Brody, E. N. (2017) · Journal of Critical Care · doi:10.1016/j.jcrc.2017.09.012 · Cited by 73
“Some of the products under control of HIF-1α inhibit the TCA cycle even when oxygen is present [24,25].”
BackgroundMeng, X., Dunsmore, G., Koleva, P. T., Elloumi, Y., Wu, R., Sutton, R. T., Ambrosio, L., Hotte, N., Nguyen, V. V., Madsen, K. L., et al. (2018) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjy186 · Cited by 72
The Tricarboxylic Acid Cycle at the Crossroad Between Cancer and Immunity
Scagliola, A., Mainini, F., & Cardaci, S. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7974 · Cited by 75
“4) (104).”
Mitochondrial dynamics in cancer stem cells
Sessions, D. T., & Kashatus, D. F. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03773-2 · Cited by 75
Mutation of SDHB is a Cause of Hypoxia-Related High-Altitude Paraganglioma
Cerecer-Gil, N. Y., Figuera, L. E., Llamas, F. J., Lara, M., Escamilla, J. N., Ramos, R., Estrada, G., Hussain, A. K., Gaal, J., Korpershoek, E., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-0637 · Cited by 70
“Oxygen normally facilitates the degradation of HIF-1 due to hydroxylation by oxygen-dependent PHD and targeting of a VHL-E3 ubiquitin-protein ligase degradation complex.”
BackgroundInfluentialImaging of tumor glucose utilization with positron emission tomography
Bürkle, A., & Weber, W. (2008) · Cancer and Metastasis Reviews · doi:10.1007/s10555-008-9151-x · Cited by 72
“Accumulation of succinate reduces activity of PHD by product inhibition [71].”
BackgroundDeletion of the Mitochondrial Chaperone TRAP-1 Uncovers Global Reprogramming of Metabolic Networks
Lisanti, S., Tavecchio, M., Chae, Y. C., Liu, Q., Brice, A. K., Thakur, M. L., Languino, L. R., & Altieri, D. C. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.06.061 · Cited by 69
“, 2012) or stabilize oncogenes, such as HIF1a (Selak et al., 2005), this has suggested that mitochondrial bioenergetics has limited (if any) role in cancer (Ward and Thompson, 2012) and may actually function as a ‘‘tumor suppressor’’ (Frezza et al.”
BackgroundHardonnière, K., Saunier, E. F., Lemarié, A., Fernier, M., Gallais, I., Héliès‐Toussaint, C., Mograbi, B., Antonio, S., Bénit, P., Rustin, P., et al. (2016) · Scientific Reports · doi:10.1038/srep30776 · Cited by 72
“This can then favor cell survival notably by activating the hypoxia-inducible factor-1 α (HIF-1 α ) transcription factor 49 .”
Distinct expression profile in fumarate-hydratase-deficient uterine fibroids
Vanharanta, S., Pollard, P. J., Lehtonen, H. J., Laiho, P., Sjöberg, J., Leminen, A., Aittomäki, K., Arola, J. T., Kruhøffer, M., Orntoft, T. F., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi431 · Cited by 73
“The mechanisms leading from defects in mitochondrial metabolism to tumorigenesis are still far from well understood, although some hypotheses related to increased reactive oxygen species production (6) and stabilization of HIF-1a (7) have been proposed.”
BackgroundKluckova, K., Sticha, M., Cerny, J., Mracek, T., Dong, L., Drahota, Z., Gottlieb, E., Neuzil, J., & Rohlena, J. (2015) · Cell Death & Disease · doi:10.1038/cddis.2015.110 · Cited by 66
“To confirm these findings in intact cells, we determined the steady-state levels of intracellular succinate, a proxy for CII activity.(27) As shown in Figure 3b, succinate concentration in WT, I56F and S68A cells was low, consistent with fully functional CII.”
BackgroundResultSelf-citationGenetics of Acromegaly and Gigantism
Bogusławska, A., & Korbonits, M. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10071377 · Cited by 71
“Germline mutation of SDH results in the accumulation of oncometabolites that inhibit degradation of hypoxia transcription factor (HIFα) [149].”
BackgroundBarth, S., Edlich, F., Berchner‐Pfannschmidt, U., Gneuss, S., Jahreis, G., Hasgall, P. A., Fandrey, J., Wenger, R. H., & Camenisch, G. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.032631 · Cited by 70
Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1
McCarty, M. F., DiNicolantonio, J. J., & O’Keefe, J. H. (2015) · Medical Hypotheses · doi:10.1016/j.mehy.2015.08.002 · Cited by 74
“prolyl hydroxylases is expected to increase the level of HIF-1a, enhancing its transcriptional activity [7,8].”
BackgroundLussey‐Lepoutre, C., Bellucci, A., Morin, A., Buffet, A., Amar, L., Janin, M., Ottolenghi, C., Zinzindohoué, F., Autret, G., Burnichon, N., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1576 · Cited by 76
“Succinate acts as an oncometabolite and is suspected to mediate most, if not all, of the tumorigenic effects related to SDHx mutations (9, 13, 14).”
BackgroundPHD2: from hypoxia regulation to disease progression
Wielockx, B., & Meneses, A. (2016) · Hypoxia · doi:10.2147/hp.s53576 · Cited by 72
“In this regard, the generation of inhibitory TCA intermediates such as fumarate, isocitrate, and succinate by damaged mitochondria is an important inhibitory factor to the PHD activity, as these molecules compete against 2-OG for the binding to the active site.(41,42) The mechanism through which these molecules exert…”
Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2
Borodovsky, A., Seltzer, M. J., & Riggins, G. J. (2011) · Current Opinion in Oncology · doi:10.1097/cco.0b013e32834d816a · Cited by 71
Metabolic re-patterning in COPD airway smooth muscle cells
Michaeloudes, C., Kuo, C. S., Haji, G. S., Finch, D. K., Halayko, A. J., Kirkham, P., Chung, K. F., & Adcock, I. M. (2017) · European Respiratory Journal · doi:10.1183/13993003.00202-2017 · Cited by 69
“Metabolic reprogramming is known to be driven by mitochondrial dysfunction and pathways such as the PI3K/Akt, mTOR and hypoxia-inducible factor-1 α , which play a key role in COPD pathogenesis [10, 11, 39].”
Succinate dehydrogenase: Prospect for neurodegenerative diseases
Farshbaf, M. J., & Kiani‐Esfahani, A. (2017) · Mitochondrion · doi:10.1016/j.mito.2017.12.002 · Cited by 71
Role of tyrosine phosphorylation in modulating cancer cell metabolism
Taddei, M. L., Pardella, E., Pranzini, E., Raugei, G., & Paoli, P. D. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188442 · Cited by 70
EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells
Roy, S., Rizvi, Z. A., Clarke, A. J., Macdonald, F., Pandey, A., Zaiss, D. M. W., Simon, A. K., & Awasthi, A. (2021) · Nature Communications · doi:10.1038/s41467-021-23042-x · Cited by 70
Integrative metabonomics as potential method for diagnosis of thyroid malignancy
Tian, Y., Nie, X., Xu, S., Li, Y., Huang, T., Tang, H., & Wang, Y. (2015) · Scientific Reports · doi:10.1038/srep14869 · Cited by 68
“Mutations in fumarate hydratase and succinate dehydrogenase have been found previously in human tumors 32–34 , which could explain our observed changes in the levels of TCA cycle intermediates in thyroid lesions.”
Cagnone, G., Dufort, I., Vigneault, C., & Sirard, M. (2011) · Biology of Reproduction · doi:10.1095/biolreprod.111.094391 · Cited by 70
“The observed HIF1A up-regulation and the associated Warburg effect [91–94] may result from mitochondria failing to perform OX-PHOS in treated embryos.”
BackgroundMechanism of Cancer Cell Adaptation to Metabolic Stress
Liu, R. R., Li, Z., Bai, S., Zhang, H., Tang, M., Lei, Y., Chen, L., Liang, S., Zhao, Y., Wei, Y., et al. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m800195-mcp200 · Cited by 70
“Enhanced aerobic glycolysis was observed in cancer cells as early as the 1930s (16), and evidence linking disordered energy metabolism and carcinogenesis is accumulating (17, 18 ).”
BackgroundBalancing biosynthesis and bioenergetics: metabolic programs in oncogenesis
Barger, J. F., & Plas, D. R. (2010) · Endocrine Related Cancer · doi:10.1677/erc-10-0106 · Cited by 65
“An important advance was the demonstration that SDHdeficient cells accumulate increased succinate, impairing PHD activity and triggering HIF-1a accumulation (Selak et al. 2005).”
ROS generation and multiple forms of mammalian mitochondrial glycerol-3-phosphate dehydrogenase
Mráček, T., Holzerová, E., Drahota, Z., Kovářová, N., Vrbacký, M., Ješina, P., & Houštěk, J. (2013) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2013.08.007 · Cited by 71
“5 mM in the tissues [19] or even in the micromolar range for cells in tissue culture [20,21].”
BackgroundMetabolic Relationship between Cancer-Associated Fibroblasts and Cancer Cells
Sazeides, C., & Le, A. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-77736-8_11 · Cited by 73
Evolving concepts in pheochromocytoma and paraganglioma
Dahia, P. L. M. (2005) · Current Opinion in Oncology · doi:10.1097/01.cco.0000198017.45982.06 · Cited by 69
HIF and fumarate hydratase in renal cancer
Sudarshan, S., Linehan, W. M., & Neckers, L. (2007) · British Journal of Cancer · doi:10.1038/sj.bjc.6603547 · Cited by 70
“Furthermore, these investigators demonstrated that succinate is able to inhibit HPH directly, most likely via product feedback inhibition (Selak et al, 2005).”
BackgroundThe von Hippel-Lindau Tumor Suppressor Protein: Roles in Cancer and Oxygen SensingPreprint
Kaelin, W. G. (2005) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2005.70.001 · Cited by 71
Hoerner, C. R., Chen, V. J., & Fan, A. C. (2019) · Kidney Cancer · doi:10.3233/kca-180043 · Cited by 68
Breast tumor and stromal cell responses to TGF-β and hypoxia in matrix deposition
Curran, C. S., & Keely, P. J. (2012) · Matrix Biology · doi:10.1016/j.matbio.2012.11.016 · Cited by 71
“…(insulin, growth factors, cytokines), increased free radical production, and cellular changes in iron and/or metabolic homeostasis (Cascio et al., 2008; Knowles and Harris, 2001; Lopez-Lazaro, 2009; Schulze and Downward, 2011; Selak et al., 2005; Spangenberg et al., 2006; Thornton et al., 2000).”
BackgroundNatural Product-Derived Small Molecule Activators of Hypoxia-Inducible Factor-1 (HIF-1)
Nagle, D. G., & Zhou, Y. (2006) · Current Pharmaceutical Design · doi:10.2174/138161206777698783 · Cited by 68
Blank, A., Schmitt, A. M., Korpershoek, E., van Nederveen, F. H., Rudolph, T. J., Weber, N., Strebel, R. T., de Krijger, R. R., Komminoth, P., & Perren, A. A. (2010) · Endocrine Related Cancer · doi:10.1677/erc-09-0316 · Cited by 67
“This is thought to cause upregulation of Hif targets leading to tumourigenesis (Dahia et al. 2005, Selak et al. 2005, 2006) in SDH-associated PCCs/PGLs.”
BackgroundHypoxia-regulated mechanisms in the pathogenesis of obesity and non-alcoholic fatty liver disease
Lefere, S., Steenkiste, C. V., Verhelst, X., Vlierberghe, H. V., Devisscher, L., & Geerts, A. M. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2222-1 · Cited by 70
“PHDs not only sense oxygen but also various metabolites, such as citric acid cycle intermediates and reactive oxygen species [64, 65], whereas HIF-1a expression is, for example, also affected by adipocyte differentiation and insulin levels [66].”
BackgroundLoss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate
Goncalves, J., Moog, S., Morin, A., Gentric, G., Müller, S., Morrell, A. P., Kľučková, K., Stewart, T. J., Andoniadou, C. L., Lussey‐Lepoutre, C., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-2936 · Cited by 77
“The role of succinate as an oncometabolite was initially demonstrated in 2005, with the demonstration of its inhibiting role on 2OG-dependent PHD enzymes, leading to the subsequent stabilization of HIFa subunits even under normoxia (43, 44).”
BackgroundTao, H., Zhong, X., Zeng, A., & Song, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1208870 · Cited by 77
Targeting cancer metabolic pathways for improving chemotherapy and immunotherapy
Luo, Z., Eichinger, K. M., Zhang, A., & Li, S. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216396 · Cited by 71
Itaconate in host inflammation and defense
Ye, D., Wang, P., Chen, L., Guan, K., & Xiong, Y. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.02.004 · Cited by 72
Enzymatic features of the glucose metabolism in tumor cells
Herling, A., König, M., Bulik, S., & Holzhütter, H. (2011) · FEBS Journal · doi:10.1111/j.1742-4658.2011.08174.x · Cited by 70
Reinke, S. N., Walsh, B. H., Boylan, G. B., Sykes, B. D., Kenny, L. C., Murray, D. M., & Broadhurst, D. (2013) · Journal of Proteome Research · doi:10.1021/pr400617m · Cited by 67
Marden, J. H. (2013) · Molecular Ecology · doi:10.1111/mec.12534 · Cited by 66
“…increased metabolite concentrations, constitutive activation of the HIF pathway (pseudohypoxia: GimenezRoqueplo et al. 2001; Pollard et al. 2005; Selak et al. 2005; Baysal et al. 2007; Smith et al. 2007; Bellance et al. 2009; Zhao et al. 2009; Puissegur et al. 2011) and develop vascularized…”
BackgroundInfluentialLee, S. Y., Ju, M. K., Jeon, H. M., Lee, Y. J., Kim, C. H., Park, H. G., Han, S. I., & Kang, H. S. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/1027453 · Cited by 69
“In addition, IDH1 mutation also leads to HIF-1α stabilization by inhibition of prolyl hydroxylase, which hydroxylates HIF-1α and uses α-ketoglutarate as a substrate allowing for the proteasomal degradation of HIF-1α [347, 351, 352].”
BackgroundMito-Nuclear Communication by Mitochondrial Metabolites and Its Regulation by B-Vitamins
Janssen, J. J. E., Grefte, S., Keijer, J., & de Boer, V. C. J. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00078 · Cited by 70
“…via EGLN inhibition (Figure 3) (Gimenez-Roqueplo et al., 2001; Briere et al., 2005; Dahia et al., 2005; Isaacs et al., 2005; Pollard et al., 2005; Selak et al., 2005; Koivunen et al., 2007), although succinate was also found to alter EGLN activity via a HIF-independent mechanism (Lee et al.,…”
BackgroundTumor-on-a-chip models combined with mini-tissues or organoids for engineering tumor tissues
Hwangbo, H., Chae, S., Kim, W.-J., Jo, S., & Kim, G. (2023) · Theranostics · doi:10.7150/thno.90093 · Cited by 71
“Previous studies have shown, that prolyl hydroxyl inhibitors can normalize tumor blood vessels, thereby improving cancer treatment efficacy [105, 106].”
BackgroundIncreases in mitochondrial biogenesis impair carcinogenesis at multiple levels
Wang, X., & Moraes, C. T. (2011) · Molecular Oncology · doi:10.1016/j.molonc.2011.07.008 · Cited by 67
Early hemorrhage triggers metabolic responses that build up during prolonged shock
D’Alessandro, A., Moore, H. B., Moore, E. E., Wither, M. J., Nemkov, T. G., González, E., Slaughter, A. L., Fragoso, M., Hansen, K. C., Silliman, C. C., et al. (2015) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00030.2015 · Cited by 66
“Moreover, TCA cycle intermediates might also promote hypoxic responses by inhibiting the enzyme prolyl hydroxylase, thereby preventing degradation and promoting stabilization of hypoxia-inducible factor 1 (HIF-1 ) (41).”
BackgroundPheochromocytoma: The First Metabolic Endocrine Cancer
Jochmanová, I., & Pacák, K. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0606 · Cited by 66
“SDHBmutations in particular were reported to cause a significant increase in ROS production and mitochondrial DNA mutability (70, 71), although pseudohypoxia can be observed in SDH-suppressed cells, even in the absence of oxidative stress (61, 72).”
BackgroundMetabolic implications of hypoxia and pseudohypoxia in pheochromocytoma and paraganglioma
Kľučková, K., & Tennant, D. A. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2801-6 · Cited by 68
“However, the experimental evidence for increased ROS in various models of SDH dysfunction is not consistent, with evidence suggesting that they are increased (Guzy et al. 2008; Ishii et al. 2005; Saito et al. 2016) or normal (Cervera et al. 2008; Selak et al. 2005).”
BackgroundBerends, A. M. A., Eisenhofer, G., Fishbein, L. M., van der Horst‐Schrivers, A. N. A., Kema, I. P., Links, T. P., Lenders, J. W. M., & Kerstens, M. N. (2019) · Cancers · doi:10.3390/cancers11081121 · Cited by 68
Cellular oxygen sensing in health and disease
Mole, D. R., & Ratcliffe, P. J. (2007) · Pediatric Nephrology · doi:10.1007/s00467-007-0632-x · Cited by 67
Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes
Nomoto, H., Pei, L., Montemurro, C., Rosenberger, M., Furterer, A., Coppola, G., Nadel, B. B., Pellegrini, M. A., Gurlo, T., Butler, P. C., et al. (2019) · Diabetologia · doi:10.1007/s00125-019-05030-5 · Cited by 70
Role of PKM2-Mediated Immunometabolic Reprogramming on Development of Cytokine Storm
Liu, Z., Le, Y., Chen, H., Zhu, J., & Lu, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.748573 · Cited by 66
“Reports indicated that PKM2 dimer can stabilize and activate HIF-1a (54), while its tetramer form counteracts excessive rate of glycolysis.”
BackgroundMoriconi, C., Dzieciątkowska, M., Roy, M. K., D’Alessandro, A., Roingeard, P., Lee, J., Gibb, D. R., Tredicine, M., McGill, M. A., Qiu, A., et al. (2022) · British Journal of Haematology · doi:10.1111/bjh.18287 · Cited by 64
Succinate and inosine coordinate innate immune response to bacterial infection
Jiang, M., Chen, Z., Li, H., Zhang, T., Yang, M., Peng, X., & Peng, B. (2022) · PLoS Pathogens · doi:10.1371/journal.ppat.1010796 · Cited by 64
“Interactions between HIF-1α prolyl hydroxylase, HIF-1α, succinate, and inosine Previous studies indicate that succinate inhibits HIF-1α prolyl hydroxylase (PHD), which destabilizes HIF-1α and promotes its degradation via the proteasome [19, 34].”
BackgroundOxygen-sensing by arterial chemoreceptors: Mechanisms and medical translation
López‐Barneo, J., Ortega‐Sáenz, P., González‐Rodríguez, P., Fernández-Agüera, M. C., Macías, D., Pardal, R., & Gao, L. (2015) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2015.12.002 · Cited by 65
Wang, H., Chen, Y., & Wu, G. (2016) · Translational Oncology · doi:10.1016/j.tranon.2016.09.009 · Cited by 64
“inhibitor of the hypoxia-inducible factor (HIF) prolyl-hydroxylases [9].”
BackgroundDysregulated metabolic enzymes and metabolic�reprogramming in cancer cells (Review)
Sreedhar, A., & Zhao, Y. (2017) · Biomedical Reports · doi:10.3892/br.2017.1022 · Cited by 71
Liu, Q., Zhuang, Y., Song, X., Niu, Q., Sun, Q., Li, X., Li, N., Liu, B., Huang, F., & Qiu, Z. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-00535-x · Cited by 67
Cancer cell metabolism: Rewiring the mitochondrial hub
Oliveira, G. L., Coelho, A. R., Marques, R., & Oliveira, P. J. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.166016 · Cited by 65
Metabolic switches during development and regeneration
Mahmoud, A. I. (2023) · Development · doi:10.1242/dev.202008 · Cited by 65
Prolyl hydroxylase domain enzymes: important regulators of cancer metabolism
Pollard, P. J., Yang, M. H., Su, H., Soga, T., & Kranc, K. R. (2014) · Hypoxia · doi:10.2147/hp.s47968 · Cited by 66
Niatsetskaya, Z. V., Basso, M., Speer, R. E., McConoughey, S. J., Coppola, G., Ma, T. C., & Ratan, R. R. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2800 · Cited by 64
“Prior studies have shown that pharmacological or molecular suppression of SDH by 3-NP or siRNA to SDH subunits leads to a cytosolic buildup of succinate and competitive inhibition of HIF PHDs (29).”
BackgroundMetabolic synthetic lethality in cancer therapy
Zecchini, V. R., & Frezza, C. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.12.003 · Cited by 63
HIF, a missing link between metabolism and cancer
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“Interestingly, succinate (the metabolite that is dehydrogenated to form fumarate in the TCA cycle) has also been shown to inhibit HIF prolyl hydroxylases, which could explain the mechanism of tumor formation in patients with germline mutations of SDH”
BackgroundNutritional Exchanges Within Tumor Microenvironment: Impact for Cancer Aggressiveness
Comito, G., Ippolito, L., Chiarugi, P., & Cirri, P. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00396 · Cited by 60
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“Both succinate and fumarate, metabolites of these enzymes, have been shown to increase HIF-1> protein levels by PHD inhibition (51, 52).”
SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors
Italiano, A., Chen, C.-L., Sung, Y., Singer, S., DeMatteo, R. P., LaQuaglia, M. P., Besmer, P., Socci, N. D., & Antonescu, C. R. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-408 · Cited by 65
“Mutations of one of the gene encoding these subunits impair the activity of this complex and lead to the stabilization and activation of HIF-1a, which in turn activates cell proliferation and angiogenesis [12-15].”
BackgroundPrediction of gastric cancer metastasis through urinary metabolomic investigation using GC/MS
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“Succinate also inhibits hypoxia-inducible factor 1 alpha (HIF-1a)-prolyl hydroxylases in the cytosol that leads at the end into stabilization and activation of HIF-1a (Selak et al., 2005).”
BackgroundLinking Metabolic Reprogramming, Plasticity and Tumor Progression
Shuvalov, O., Daks, A., Fedorova, O., Petukhov, A., & Barlev, N. (2021) · Cancers · doi:10.3390/cancers13040762 · Cited by 63
“Another mechanism that mediates progression of tumors with FH and SDHx mutations relies on the intracellular accumulation of both fumarate and succinate, which consequently promote HIF1a stabilization [164,165] and execution of its transcriptional program.”
BackgroundHypoxia-Inducible Factor in Thyroid Carcinoma
Burrows, N., Babur, M., Resch, J., Williams, K. J., & Brabant, G. E. (2011) · Journal of Thyroid Research · doi:10.4061/2011/762905 · Cited by 66
“Both fumarate and succinate inhibit PHDs by competing with 2-OG for binding to the active site [20, 21].”
BackgroundSignaling Pathways in Pheochromocytomas and Paragangliomas: Prospects for Future Therapies
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“Succinate stabilises and activates HIF-1α by inhibiting prolyl hydroxylase in tumours [28]; it thus reprogrammes energy metabolism under anoxic conditions.”
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“…and glucose transporters), and 536 promotes lactic acid production (e.g., via regulation of lactate dehydrogenase and 537 monocarboxylate transporter 4) (Ben-Shlomo et al. 1997; Selak et al. 2005; Semenza 2010; 538 Palsson-McDemott & O’Neill 2013; Tannahill et al. 2013; Mills & O’Neill 2014).”
BackgroundReceptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91
Trauelsen, M., Ulven, E. R., Hjorth, S. A., Brvar, M., Monaco, C. G., Frimurer, T. M., & Schwartz, T. W. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.09.005 · Cited by 63
“Importantly, independent of GPR91 signaling, succinate can cause a number of intracellular responses, including post translational modifications [20], HIF-1a stabilization [21], production of mitochondrial reactive oxygen species (ROS) [11], and overall changes to cellular metabolism owing to its central role in the T…”
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Reporter Ligand NMR Screening Method for 2-Oxoglutarate Oxygenase Inhibitors
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Mitochondrial Dysfunction Impairs Tumor Suppressor p53 Expression/Function
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“However, this ROS production is supported by what are probably high concentrations of exogenously added succinate; there are indications that endogenous succinate concentrations (from the citric acid cycle) may be much lower [13,55,56].”
BackgroundThe Mitochondrial Respiratory Chain Is Required for Organismal Adaptation to Hypoxia
Hamanaka, R. B., Weinberg, S. E., Reczek, C. R., & Chandel, N. S. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.03.044 · Cited by 63
“…and production of ROS have all been demonstrated to regulate the activity of HIF prolyl hydroxylases (Bell et al., 2007; Brunelle et al., 2005; Guzy et al., 2005; Hagen et al., 2003; Isaacs et al., 2005; Mansfield et al., 2005; Pan et al., 2007; Selak et al., 2005; Sullivan et al., 2013).”
InfluentialActivation of Vibrio cholerae quorum sensing promotes survival of an arthropod host
Kamareddine, L., Wong, A. C.-N., Vanhove, A. S., Hang, S., Purdy, A. E., Kierek, K., Asara, J. M., Ali, A., Morris, J. G., & Watnick, P. I. (2017) · Nature Microbiology · doi:10.1038/s41564-017-0065-7 · Cited by 55
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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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