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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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“Generally termed ‘metabolic signaling’ (Gottlieb and Tomlinson, 2005), it was initiated by the identification of an intracellular signal transduction cascade that is mediated by TCA cycle metabolites (Isaacs et al., 2005; Selak et al., 2005).”
BackgroundSelf-citationCancer Metabolism: Current Understanding and Therapies
Counihan, J. L., Grossman, E. A., & Nomura, D. K. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00775 · Cited by 236
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Increased risk of cancer in patients with fumarate hydratase germline mutation
Lehtonen, H. J., Kiuru, M. H., Ylisaukko‐oja, S. K., Salovaara, R., Herva, R., Koivisto, P., Vierimaa, O., Aittomäki, K., Pukkala, ., Launonen, V., et al. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2005.036400 · Cited by 232
Regulatory mechanisms of hypoxia‐inducible factor 1 activity: Two decades of knowledge
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“Loss-of-function mutations in SDH and FH, which have been detected in “hereditary paraganglioma” and “hereditary leiomyomatosis and renal cell cancer”, were shown to cause abnormal accumulation of succinate and fumarate, respectively.(23,24) The accumulated metabolites inhibited PHD through product inhibition, whereby…”
BackgroundMetabolic transformation in cancer
Tennant, D. A., Durán, R. V., Boulahbel, H., & Gottlieb, E. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp070 · Cited by 235
Self-citationWaves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells
Smolková, K., Plecitá‐Hlavatá, L., Bellancé, N., Bénard, G., Rossignol, R., & Ježek, P. (2010) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2010.05.003 · Cited by 232
Ni, Y., Zbuk, K. M., Sadler, T. M., Patócs, A., Lobo, G. P., Edelman, E. A., Platzer, P., Orloff, M. S., Waite, K. A., & Eng, C. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.07.011 · Cited by 223
“This inhibition could contribute to stabilization of HIF and promote transcription of genes containing hypoxic response elements.(29) An alternative hypothesis is that mutations in SDH result in increased ROS.”
MethodFumarate is a terminal electron acceptor in the mammalian electron transport chain
Spinelli, J. B., Rosen, P. C., Sprenger, H.-G., Puszynska, A. M., Mann, J. L., Roessler, J. M., Cangelosi, A. L., Henne, A., Condon, K. J., Zhang, T., et al. (2021) · Science · doi:10.1126/science.abi7495 · Cited by 221
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“In the presence of oxygen, iron, or 2-oxoglutarate, PHDs hydroxylate specific proline residues within the oxygen-dependent domain of HIF-1a, enabling its binding to the von Hippel-Landau tumor suppressor protein, a component of the E3 ubiquitin ligase complex that leads to the ubiquitination and subsequent proteasome-…”
BackgroundInfluentialHypoxia-dependent regulation of inflammatory pathways in immune cells
Taylor, C. T., Doherty, G. A., Fallon, P. G., & Cummins, E. P. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84433 · Cited by 225
“Dysregulation of metabolic enzymes involved in the production of these intermediates in the tumor setting are associated with altered HIF-dependent signaling (24, 25).”
BackgroundCancer Cell MetabolismPreprint
Cairns, R. A., Harris, I. S., McCracken, S. A., & Mak, T. W. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.012856 · Cited by 229
“Constitutively active Akt1 can activate HIF1 even under normoxic conditions (Inoki et al. 2005; Plas and Thompson 2005; Lu et al. 2008), as can a deficiency of pVHL (Kaelin 2008; Kapitsinou and Haase 2008), succinic dehydrogenase, or fumarate hydratase (Selak et al. 2005; King et al. 2006).”
BackgroundZdzisińska, B., Żurek, A., & Kandefer-Szerszeń, M. (2017) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-016-0406-x · Cited by 221
“These compounds compete with AKG in binding to PHD2, and when bound to the enzyme they inhibit its activity, which in turn contributes to stabilisation of HIF-1a and activation of genes that promote carcinogenesis (Brière et al. 2005; Isaacs et al. 2005; Pollard et al. 2005; Pugh and Ratcliffe 2003; Selak et al. 2005).”
BackgroundPayen, V. L., Porporato, P. E., Baselet, B., & Sonveaux, P. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2098-5 · Cited by 226
Oncometabolites in renal cancer
Yong, C., Stewart, G. D., & Frezza, C. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0210-z · Cited by 216
Hypoxia, HIF-1α, and COVID-19: from pathogenic factors to potential therapeutic targets
Serebrovska, Z. O., Chong, E., Serebrovskaya, T. V., Tumanovska, L. V., & Xi, L. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-00554-8 · Cited by 220
Is cancer a disease of abnormal cellular metabolism? New angles on an old idea
DeBerardinis, R. J. (2008) · Genetics in Medicine · doi:10.1097/gim.0b013e31818b0d9b · Cited by 225
Kelly, T. J., Souza, A. L., Clish, C. B., & Puigserver, P. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01242-10 · Cited by 222
Ebbesen, P., Pettersen, E. O., Gorr, T. A., Jobst, G., Williams, K. J., Kieninger, J., Wenger, R. H., Pastoreková, S., Dubois, L. J., Lambin, P., et al. (2009) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756360902784425 · Cited by 221
Head and neck paragangliomas: clinical and molecular genetic classification
Offergeld, C., Brase, C., Yaremchuk, S., et al. (2012) · Clinics · doi:10.6061/clinics/2012(sup01)05 · Cited by 218
Sudarshan, S., Sourbier, C., Kong, H.-S., Block, K., Romero, V. A. V., Yang, Y., Galindo, C., Mollapour, M., Scroggins, B., Goode, N., et al. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00483-09 · Cited by 217
Single-Gene Disorders: What Role Could Moonlighting Enzymes Play?
Sriram, G., Martínez-Agosto, J. A., McCabe, E. R. B., Liao, J. C., & Dipple, K. M. (2005) · The American Journal of Human Genetics · doi:10.1086/430799 · Cited by 218
“…of SDH, metabolic activity may be indirectly responsible for tumor suppression; succinate, which accumulates as a re- sult of SDH deficiency, inhibits hypoxia-inducible factor 1a (HIF-1a) prolyl hydroxylases, thereby stabilizing HIF1a, which causes angiogenesis and tumor growth (Selak et al. 2005).”
BackgroundCancer metabolism in space and time: Beyond the Warburg effect
Danhier, P., Bański, P., Payen, V. L., Grasso, D., Ippolito, L., Sonveaux, P., & Porporato, P. E. (2017) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2017.02.001 · Cited by 230
Hypoxia/pseudohypoxia‐mediated activation of hypoxia‐inducible factor‐1α in cancer
Hayashi, Y., Yokota, A., Harada, H., & Huang, G. (2019) · Cancer Science · doi:10.1111/cas.13990 · Cited by 229
Exploring the molecular interface between hypoxia-inducible factor signalling and mitochondria
Thomas, L. W., & Ashcroft, M. A. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03039-y · Cited by 219
“Elevated levels of succinate are capable of inhibiting the hydroxylation reaction [141], as is elevation in the levels of a second TCA cycle intermediate, fumarate [142].”
BackgroundNon-heme dioxygenases: cellular sensors and regulators jelly rolled into one?
Ozer, A., & Bruick, R. K. (2007) · Nature Chemical Biology · doi:10.1038/nchembio863 · Cited by 214
“On the other hand, other TCA intermediates, such as succinate and fumarate, can inhibit hydroxylase activity by product inhibition or by competition for binding with 2-oxoglutarat”
BackgroundPugliese, S. C., Poth, J. M., Fini, M. A., Olschewski, A., Kasmi, K. C. E., & Stenmark, K. R. (2014) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00238.2014 · Cited by 220
Macrophage function in obesity-induced inflammation and insulin resistance
Lauterbach, M., & Wunderlich, F. T. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1955-5 · Cited by 216
“In certain cancer cells that exhibit Warburg metabolism, inhibition of PHDs can lead to HIF1α stabilization under normoxic conditions [97].”
BackgroundRegulation of succinate dehydrogenase and role of succinate in cancer
Dalla Pozza, E., Dando, I., Pacchiana, R., Liboi, E., Scupoli, M. T., Donadelli, M., & Palmieri, M. (2020) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2019.04.013 · Cited by 212
Hypoxia, Metabolism and Immune Cell Function
Krzywińska, E., & Stockmann, C. (2018) · Biomedicines · doi:10.3390/biomedicines6020056 · Cited by 216
Dong, L.-F., Jameson, V. J. A., Tilly, D., Cerny, J., Mahdavian, E., Marín-Hernández, A., Hernández-Esquivel, L., Rodríguez-Enríquez, S., Stursa, J., Witting, P. K., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.186643 · Cited by 200
van Gisbergen, M. W., Voets, A. M., Starmans, M. H. W., de Coo, I. F. M., Yadak, R., Hoffmann, R. F., Boutros, P. C., Smeets, H. J. M., Dubois, L. J., & Lambin, P. (2015) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2015.01.001 · Cited by 207
“Although, evidence for a causative role of the latter mentioned mutations in oncogenesis is mostly indirect, the consequent changes in metabolite levels such as succinate have been shown to influence hypoxia inducible factor (HIF) stabilization [58].”
Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions
Vernieri, C., Casola, S., Foiani, M., Pietrantonio, F., de Braud, F., & Longo, V. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0615 · Cited by 202
Cytokine-like Roles for Metabolites in Immunity
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Mechanisms of adaptive angiogenesis to tissue hypoxia
Fong, G. (2008) · Angiogenesis · doi:10.1007/s10456-008-9107-3 · Cited by 212
15 YEARS OF PARAGANGLIOMA: Clinical manifestations of paraganglioma syndromes types 1–5
Benn, D. E., Robinson, B. G., & Clifton-Bligh, R. J. (2015) · Endocrine Related Cancer · doi:10.1530/erc-15-0268 · Cited by 200
“Both outcomes have been suggested to contribute to cellular accumulation of hypoxia-inducible factors (Selak et al. 2005), and tumours associated with SDH deficiency display notable upregulation of hypoxia- responsive genes.”
BackgroundThe hypoxia‐inducible‐factor hydroxylases bring fresh air into hypoxia signalling
Berra, E., Ginouvès, A., & Pouysségur, J. (2006) · EMBO Reports · doi:10.1038/sj.embor.7400598 · Cited by 205
“Mutations in the tumour suppressor succinate dehydrogenase (SDH) have also been linked to PHDs (Selak et al, 2005; Lee et al, 2005); succinate, which accumulates as a result of SDH mutations, inhibits PHD activity.”
BackgroundOxidative Stress and MicroRNAs in Vascular Diseases
Magenta, A., Greco, S., Gaetano, C., & Martelli, F. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140917319 · Cited by 198
Ai, Z., Lü, Y., Qiu, S., & Fan, Z. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.01.009 · Cited by 196
Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications
Wei, Q., Qian, Y., Yu, J. Q., & Wong, C. C. (2020) · Oncogene · doi:10.1038/s41388-020-01432-7 · Cited by 193
“First is by stabilization of HIF in cancer cells through inhibition of HIF prolyl-hydroxylase, an α-KG-dependent dioxygenase [79].”
MethodMaynard, M. A., Evans, A. J., Hosomi, T., Hara, S., Jewett, M. A. S., & Ohh, M. (2005) · The FASEB Journal · doi:10.1096/fj.05-3788com · Cited by 205
Recurrent epimutation of SDHC in gastrointestinal stromal tumors
Killian, J. K., Miettinen, M., Walker, R. L., Wang, Y., Zhu, Y. J., Waterfall, J. J., Noyes, N., Retnakumar, P., Yang, Z., Smith, W. I., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009961 · Cited by 194
You, Y.-H., Quach, T., Saito, R., Pham, J., & Sharma, K. (2015) · Journal of the American Society of Nephrology · doi:10.1681/asn.2015030302 · Cited by 191
Intermediates of Metabolism: From Bystanders to Signalling Molecules
Haas, R., Cucchi, D., Smith, J., Pucino, V., Macdougall, C. E., & Mauro, C. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.02.003 · Cited by 199
“Thus, reduction of this hydroxylation results in HIF stabilisation leading to the transcription of genes involved in proliferation, angiogenesis, and metastasis [49] (Figure 3).”
BackgroundRole of mitochondrial alterations in human cancer progression and cancer immunity
Wang, S., Tseng, L., & Lee, H. (2023) · Journal of Biomedical Science · doi:10.1186/s12929-023-00956-w · Cited by 225
Reactive Oxygen Species Regulate Hypoxia-Inducible Factor 1α Differentially in Cancer and Ischemia
Qutub, A. A., & Popel, A. S. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00060-08 · Cited by 196
An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma
Buffet, A., Burnichon, N., Favier, J., & Gimenez‐Roqueplo, A. (2020) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2020.101416 · Cited by 202
Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect
Chen, Y., Cairns, R. A., Papandreou, I., Koong, A. C., & Denko, N. C. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007033 · Cited by 193
“Through genetic studies, fumarate hydrolase and succinate dehydrogenase have been shown to be tumor suppressors [19,20].”
BackgroundReactive oxygen species and cellular oxygen sensing
Cash, T. P., Pan, Y., & Simon, M. C. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.07.001 · Cited by 195
Self-citationNeuroprotection in Diet-Induced Ketotic Rat Brain after Focal Ischemia
Puchowicz, M. A., Zechel, J. L., Valerio, J., Emancipator, D., Xu, K., Pundik, S., LaManna, J. C., & Lust, W. D. (2008) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.79 · Cited by 188
“…of citric acid cycle intermediates, such as citrate and succinate, and thus we hypothesized that the metabolic side of HIF-1a regulation via ketosis is through product inhibition of PHD by succinate (Myllyla et al, 1977; Selak et al, 2005), an intermediate of energy metabolism (see Figure 7).”
Redox regulation of the hypoxia-inducible factor
Pouysségur, J., & Mechta-Grigoriou, F. (2006) · Biological Chemistry · doi:10.1515/bc.2006.167 · Cited by 186
“Since physiological changes in iron metabolism (Gerald et al., 2004; Knowles et al., 2006) or bioenergetic intermediates (Lu et al., 2005; Selak et al., 2005) have an important impact on HIF hydroxylase activity under normoxia, these newly identified mechanisms might be manipulated for therapeutic…”
BackgroundAbnormal Sympathoadrenal Development and Systemic Hypotension in PHD3−/− Mice
Bishop, T., Gallagher, D., Pascual, A., Lygate, C. A., de Bono, J. P., Nicholls, L. G., Ortega‐Sáenz, P., Oster, H., Wijeyekoon, B., Sutherland, A., et al. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.02041-07 · Cited by 186
Applications of metabolomics to study cancer metabolism
Kaushik, A. K., & DeBerardinis, R. J. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.04.009 · Cited by 179
“Mechanistically, with varying IC50 values, fumarate and succinate inhibit α-KG dependent prolyl hydroxylases[46, 47], TET enzyme-regulated hydroxylation of methyl-cytosine[48] including in the promoters of HIF-regulated genes[49], and histone demethylases[48], conferring genome and proteome modifications that support…”
Aspuria, P.-J. P., Lunt, S. Y., Väremo, L., Vergnes, L., Gozo, M. C., Beach, J. A., Salumbides, B. C., Reue, K., Wiedemeyer, W. R., Nielsen, J., et al. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-21 · Cited by 192
“This phenomenon was first described linking succinate to HIF1α stabilization; succinate was found to directly inhibit prolyl hydroxylases which serve to degrade HIF1α [48,49].”
BackgroundMetabolic Signaling to the Nucleus in Cancer
Campbell, S. L., & Wellen, K. E. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.07.015 · Cited by 186
Pollard, P. J., Spencer‐Dene, B., Shukla, D., Howarth, K. M., Nye, E. L., El-Bahrawy, M. A., Deheragoda, M. G., Kolatsi‐Joannou, M., McDonald, S. A. C., Martin, A., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.02.005 · Cited by 182
The HIF pathway and erythrocytosis
Lee, F. S., & Percy, M. J. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130321 · Cited by 177
Current and Future Treatments for Malignant Pheochromocytoma and Sympathetic Paraganglioma
Jiménez, C., ROHREN, E. M., Habra, M. A., Rich, T. A., Jiménez, P., Ayala‐Ramirez, M., & Baudin, É. (2013) · Current Oncology Reports · doi:10.1007/s11912-013-0320-x · Cited by 179
“In addition, inactivation of the mitochondrial enzymatic complex II increases intracellular concentrations of succinate, which in turn amplifies the process of pseudohypoxia by impairing the ubiquitylation of HIF by prolyl hydroxylases [20].”
BackgroundOncometabolites: Unconventional triggers of oncogenic signalling cascades
Sciacovelli, M., & Frezza, C. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.025 · Cited by 184
“For instance, succinate inhibits prolyl-hydroxylases (PHDs), aKGDDs involved in the degradation of Hypoxia Inducible Factor (HIF), leading to the aberrant stabilisation of HIFs even when oxygen is abundant, a condition called pseudohypoxia [33].”
BackgroundGermline FH Mutations Presenting With Pheochromocytoma
Clark, G. R., Sciacovelli, M., Gaude, E., Walsh, D. M., Kirby, G. A., Simpson, M. A., Trembath, R. C., Berg, J. N., Woodward, E. R., Kinning, E., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1659 · Cited by 185
Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine
Guo, L., Shestov, A. A., Worth, A. J., Nath, K., NELSON, D. S., Leeper, D. B., Glickson, J. D., & Blair, I. A. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.697516 · Cited by 187
“Accumulation of succinate resulting from complex II deficiency inhibits prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF1 (46).”
BackgroundRedox Potential of Antioxidants in Cancer Progression and Prevention
George, S., & Abrahamse, H. (2020) · Antioxidants · doi:10.3390/antiox9111156 · Cited by 187
Bernard, K. F., Logsdon, N. J., Benavides, G. A., Sanders, Y. Y., Zhang, J., Darley-Usmar, V. M., & Thannickal, V. J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.000444 · Cited by 181
“The accumulation of TCA cycle-derived metabolites succinate and fumarate have been reported to block prolyl hydroxylase activity and stabilize HIF-1α in cancer cells (46-49).”
ROS: Really involved in Oxygen Sensing
Kaelin, W. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.006 · Cited by 173
Pyruvate kinase M2: A simple molecule with complex functions
Alquraishi, M. I., Puckett, D. L., Alani, D., Humidat, A. S., Frankel, V. D., Donohoe, D. R., Whelan, J. N., & Bettaieb, A. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.08.007 · Cited by 185
Hypoxia-Inducible Factor Signaling in Pheochromocytoma: Turning the Rudder in the Right Direction
Jochmanová, I., Yang, C., Zhuang, Z., & Pacák, K. (2013) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djt201 · Cited by 177
Metabolic changes in cancer: beyond the Warburg effect
Wu, W., & Zhao, S. (2013) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gms104 · Cited by 173
Molecular targeting of hypoxia in radiotherapy
Rey, S., Schito, L., Koritzinsky, M., & Wouters, B. G. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.10.002 · Cited by 178
“[89] and 2-hydroxyglutarate; [90] these metabolites compete with α-ketoglutarate and inhibit PHDs thus enhancing HIF-1α (and -2α)”
BackgroundImpact of intracellular innate immune receptors on immunometabolism
Chou, W.-C., Rampanelli, E., Li, X., & Ting, J. P. ‐. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00780-y · Cited by 173
“Once in the cytosol, succinate inhibits prolyl hydroxylases and thus promotes HIF-1α stabilization and activation [94, 97], resulting in the upregulation of glycolytic enzymes [3, 11, 38, 98].”
BackgroundBreast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis
Isidoro, A., Casado, E., Redondo, A., Acebo, P., Espinosa, E., Alonso, A. M., Cejas, P., Hardisson, D., Vara, J. Á. F., Belda-Iniesta, C., et al. (2005) · Carcinogenesis · doi:10.1093/carcin/bgi188 · Cited by 172
“inhibits HIF-1α prolyl-hydroxylase (42), contributing in this way to the abnormal”
BackgroundIdentification of Potential Biomarkers for Ovarian Cancer by Urinary Metabolomic Profiling
Zhang, T., Wu, X., Ke, C., Yin, M., Li, Z., Fan, L., Zhang, W., Zhang, H., Zhao, F., Zhou, X., et al. (2012) · Journal of Proteome Research · doi:10.1021/pr3009572 · Cited by 169
Mitochondria and cancer: is there a morphological connection?
Alirol, E., & Martinou, J. (2006) · Oncogene · doi:10.1038/sj.onc.1209600 · Cited by 171
“An alternative model proposes that succinate, which accumulates due to TCA cycle impairment, acts as a signalling molecule and triggers the activation of hypoxia inducible factor 1a (HIF1a) (Selak et al., 2005).”
BackgroundSuccinate inhibition of α-ketoglutarate-dependent enzymes in a yeast model of paraganglioma
Smith, E. H., Janknecht, R., & Maher, L. J. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm275 · Cited by 169
Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) – A review
Miettinen, M., & Lasota, J. P. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.05.033 · Cited by 168
Biphasic Dynamics of Macrophage Immunometabolism during Mycobacterium tuberculosis Infection
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Mitochondrial pathology: stress signals from the energy factory
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Kaluz, Š., Kaluzová, M., & Stanbridge, E. J. (2008) · Clinica Chimica Acta · doi:10.1016/j.cca.2008.05.002 · Cited by 175
“Interestingly, in the hereditary cancer syndromes, hereditary paraganglioma (HPGL), and hereditary leiomyomatosis and renal cell carcinoma (HLRCC), accumulation of succinate and fumarate, respectively, due to inactivating mutations of various subunits of succinate dehydrogenase [42] and fumarate hydratase [43], result…”
BackgroundHIF1A Reduces Acute Lung Injury by Optimizing Carbohydrate Metabolism in the Alveolar Epithelium
Eckle, T. D. L. G., Brodsky, K. S., Bonney, M., Packard, T. A., Han, J., Borchers, C. H., Mariani, T. J., Kominsky, D. J., Mittelbronn, M. G. A., & Eltzschig, H. K. (2013) · PLoS Biology · doi:10.1371/journal.pbio.1001665 · Cited by 166
Burr, S. P., Costa, A. S. H., Grice, G. L., Timms, R. T., Lobb, I. T., Freisinger, P., Dodd, R. B., Dougan, G., Lehner, P. J., Frezza, C., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.015 · Cited by 155
“This was particularly intriguing, as prior studies showed that mutations in other TCA cycle enzymes inhibit PHD activity through the accumulation of TCA intermediates such as succinate (Selak et al., 2005).”
BackgroundInfluentialHypoxia‐inducible factor as a physiological regulator
Maxwell, P. H. (2005) · Experimental Physiology · doi:10.1113/expphysiol.2005.030924 · Cited by 170
“This has recently been confirmed; increasing levels of succinate or fumarate, either pharmacologically, or through genetic decreases in succinate dehydrogenase or fumarate hydratase, can induce HIF by decreasing hydroxylase activity (Isaacs et al. 2005; Selak et al. 2005).”
BackgroundXekouki, P., Pacák, K., Almeida, M. Q., Wassif, C. A., Rustin, P., Nesterova, M., Sierra, M. D. L. L., Matro, J. C., Ball, E. R., Azevedo, M. F., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1179 · Cited by 169
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Metabolic coordination of cell fate by α-ketoglutarate-dependent dioxygenases
Baksh, S. C., & Finley, L. W. S. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.09.010 · Cited by 165
“For example, succinate and fumarate accumulation in cancer cells is linked to HIF stabilization and hypermethylation of DNA as well as multiple histone lysine residues [20,22,23].”
BackgroundBayley, J., Launonen, V., & Tomlinson, I. P. M. (2008) · BMC Medical Genetics · doi:10.1186/1471-2350-9-20 · Cited by 167
Targeting cancer metabolism – aiming at a tumour's sweet-spot
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Adapt and conquer: Metabolic flexibility in cancer growth, invasion and evasion
Kreuzaler, P. A., Panina, Y., Segal, J., & Yuneva, M. O. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.08.021 · Cited by 170
“It has a number of other consequences, such as impairing HIF signaling and leading to CpG hypermethylation [73,74], which markedly influence the tumor transcriptome and metabolome.”
BackgroundLandscape of the mitochondrial Hsp90 metabolome in tumours
Chae, Y. C., Angelin, A., Lisanti, S., Kossenkov, A. V., Speicher, K. D., Wang, H., Powers, J. F., Tischler, A. S., Pacák, K., Fliedner, S. M. J., et al. (2013) · Nature Communications · doi:10.1038/ncomms3139 · Cited by 162
Oncogenic regulation of tumor metabolic reprogramming
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“In fact, deficiency of succinate dehydrogenase has been demonstrated to increase succinate levels and competitively inhibit PHDs under normoxia, leading to HIF1α stabilization in a pseudohypoxic phenotype [93].”
TCA Cycle Defects and Cancer: When Metabolism Tunes Redox State
Cardaci, S., & Ciriolo, M. R. (2012) · International Journal of Cell Biology · doi:10.1155/2012/161837 · Cited by 169
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“In the cytosol, succinate acts as a stable regulator, high concentrations of which result in inhibition of PHD (Figure 3), leading to HIF-1α stabilization and activation (56).”
A neuronal network of mitochondrial dynamics regulates metastasis
Caino, M. C., Seo, J. H., Aguinaldo, A., Wait, E. C., Bryant, K. G., Kossenkov, A. V., Hayden, J. E., Vaira, V., Morotti, A., Ferrero, S., et al. (2016) · Nature Communications · doi:10.1038/ncomms13730 · Cited by 162
“…that is hallmark of most malignancies 2 , and the characterization of ‘oncometabolites’ produced by a dysfunctional or mutant respiratory chain 18 have suggested that mitochondrial metabolism may be dispensable in malignancy, and may actually function as a ‘tumour suppressor’, at least in…”
Kaelin, W. G. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010975 · Cited by 161
“…linked to FH deficiency and to paragangliomas linked to SDH defi- ciency (Gimenez-Roqueplo et al. 2001; Isaacs et al. 2005; Pollard et al. 2005; Selak et al. 2005, 2006; MacKenzie et al. 2007; Pollard et al. 2007; Sudarshan et al. 2009, 2011), although the paucity of relevant cell culture…”
The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy
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Genetic predisposition to kidney cancer
Schmidt, L. S., & Linehan, W. M. (2016) · Seminars in Oncology · doi:10.1053/j.seminoncol.2016.09.001 · Cited by 163
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“Although 2-oxoglutarate, a tricarboxylic acid (TCA) cycle intermediate, is essential for the activity of PHDs because of its role in the coordination of iron in the catalytic core, other TCA cycle intermediates such as succinate and fumarate appear to inhibit PHDs by competing with 2-oxoglutarate for binding to the ac…”
BackgroundMitochondrial complex II and reactive oxygen species in disease and therapy
Vanova, K. H., Kraus, M., Neužil, J., & Rohlena, J. (2020) · Redox Report · doi:10.1080/13510002.2020.1752002 · Cited by 166
“ization of hypoxia-inducible factor-α [48], while others ascribed this effect to the accumulation of succinate [49].”
BackgroundMetabolic consequences of oncogenic IDH mutations
Parker, S. J., & Metallo, C. M. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.05.003 · Cited by 162
“As such, D-2HG acts in a manner similar to the succinate and fumarate that accumulate in the context of SDH and FH mutant tumors, respectively (Selak et al., 2005; Xiao et al., 2012).”
BackgroundLee, G., Won, H., Lee, Y.-M., Choi, J.-W., Oh, T.-I., Jang, J.-H., Choi, D., Lim, B. O., Kim, Y. J., Park, J., et al. (2016) · Scientific Reports · doi:10.1038/srep18928 · Cited by 166
Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk
Wang, X.-H., Xu, S., Zhou, X., Zhao, R., Lin, Y., Cao, J., Zang, W., Tao, H., Xu, W., Li, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23827-0 · Cited by 164
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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