Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.

By M. Selak, S. Armour, Elaine D. MacKenzie, Houda Boulahbel, D. G. Watson, Kyle D Mansfield, Yi Pan, M. C. Simon, Craig B. Thompson, Eyal Gottlieb. Cancer Cell, 2005

2,158 citations recorded by the source corpus.

Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha. These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.

Subfields: Cancer Research, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/69521fc4404139c922c163a8973a717305728a33

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. G. Semenza
2. C. V. Dang
3. M. V. Vander Heiden
4. Ralph J. Deberardinis
5. Craig B. Thompson
6. David M. Sabatini
7. W. Kaelin
8. Jung-whan Kim

In Molecular Biology

1. David M. Sabatini
2. G. Semenza
3. C. V. Dang
4. Ralph J. Deberardinis
5. M. V. Vander Heiden
6. Craig B. Thompson
7. W. Kaelin
8. Erika L. Pearce

In Surgery

1. G. Semenza
2. M. V. Vander Heiden
3. David M. Sabatini
4. Ralph J. Deberardinis
5. W. Kaelin
6. K. Guan
7. A. Gimenez-Roqueplo
8. Peng Huang

Citations in the corpus

• Mitochondria in the regulation of innate and adaptive immunity (2015, neutral): “, 2013), an effect that has previously been reported to occur in tumors (Selak et al., 2005).”
• SIRT5-Mediated Lysine Desuccinylation Impacts Diverse Metabolic Pathways (2013, background): “Elevated succinate levels can lead to epigenetic dysregulation (Cervera et al., 2009; Smith et al., 2007).”
• Role of Mitochondria in Ferroptosis (2018, background): “FH defect leads to aberrant accumulation of fumarate, which in turn inactivates prolyl hydroxylases and thus stabilizes hypoxia-inducible factor (HIF)-1α (Isaacs et al., 2005; Selak et al., 2005).”
• SDH mutations establish a hypermethylator phenotype in paraganglioma. (2013, background): “Succinate and fumarate can activate the oncogenic HIF pathway by inhibiting HIF prolyl-hydroxylases (Brière et al., 2005; Selak et al., 2005).”
• Metabolic reprogramming and cancer progression (2020, background): “Metabolite accumulation in the setting of dysfunctional mitochondria can inhibit VHL-dependent degradation of hypoxia-inducible factor-a (HIF-a) subunits, creating a pseudohypoxic state that mimics VHL loss (14).”
• Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases (2011, background): “Mutations targeting FH and SDH lead to similar increase in the PHD substrate, HIF-1a (Isaacs et al., 2005; Pollard et al., 2005; Selak et al., 2005).”
• HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, neutral): “…in VHL directly block the ubiquitination of HIF-α subunits, mutations in the genes encoding succinate dehydrogenase (SDH) and fumarate hydratase (FH) block ubiquitination indirectly by increasing the concentration of TCA cycle intermediates that inhibit prolyl hydroxylase activity (91–93).”
• The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. (2008, neutral): “…complex; mTOR, mammalian target of rapamycin; glc-6-P, glucose-6-phosphate; 3-PG, 3-phosphoglycerate; PDK1, pyruvate dehydrogenase kinase 1; SDH, succinate dehydrogenase; FH, fumarate hydratase; HIF-1 a , hypoxia-inducible factor 1 a ; VHL, von Hippel-Lindau. et al., 2007; Selak et al., 2005).”
• Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer (2006, background): “Although both molecules were shown to mediate HIF induction (Isaacs et al., 2005; Selak et al., 2005), it is possible that they inhibit different PHDs with different efficiency.”
• Mitochondrial tumour suppressors: a genetic and biochemical update (2005, background): “Recently, a novel pathway that links the inhibition of SDH to the induction of hypoxia-inducible factor (HIF) was identifie”
• Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages (2015, neutral): “This phenomenon, which has been described as ‘pseudo hypoxia’ takes place when excess succinate is transported out of the mitochondria into the cytosol where it can impair the activity of prolylhydroxylases (PHD) leading to stabilization and activation of Hif-1α (Selak et al., 2005).”
• Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. (2005, background): “Recently, support has been provided using an in vitro system for dysfunction of the Krebs cycle leading to the stabilization of HIF (27).”