Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase

M.A. Selak, S.M. Armour, E.D. MacKenzie, H. Boulahbel, D.G. Watson, K.D. Mansfield, Y. Pan, M.C. Simon, C.B. Thompson, E. Gottlieb

Research output: Contribution to journalArticle

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Abstract

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-α prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1α. These results suggest a mechanistic link between SDH mutations and HIF-1α induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.
LanguageEnglish
Pages77-85
Number of pages9
JournalCancer Cell
Volume7
DOIs
Publication statusPublished - 2005

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Citric Acid Cycle
Succinate Dehydrogenase
Succinic Acid
Carcinogenesis
Cytosol
Fumarate Hydratase
Prolyl Hydroxylases
Neoplasms
Mutation
Mitochondrial Proteins
Blood Vessels
Mitochondria
Enzymes

Keywords

  • tricarboxylic acid (TCA) cycle
  • succinate dehydrogenase (SDH)
  • prolylhydroxylase

Cite this

Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., ... Gottlieb, E. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase. Cancer Cell, 7, 77-85. https://doi.org/10.1016/j.ccr.2004.11.022
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. / Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase. In: Cancer Cell. 2005 ; Vol. 7. pp. 77-85.
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Selak, MA, Armour, SM, MacKenzie, ED, Boulahbel, H, Watson, DG, Mansfield, KD, Pan, Y, Simon, MC, Thompson, CB & Gottlieb, E 2005, 'Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase' Cancer Cell, vol. 7, pp. 77-85. https://doi.org/10.1016/j.ccr.2004.11.022

Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase. / 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.

In: Cancer Cell, Vol. 7, 2005, p. 77-85.

Research output: Contribution to journalArticle

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T1 - Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase

AU - Selak, M.A.

AU - Armour, S.M.

AU - MacKenzie, E.D.

AU - Boulahbel, H.

AU - Watson, D.G.

AU - Mansfield, K.D.

AU - Pan, Y.

AU - Simon, M.C.

AU - Thompson, C.B.

AU - Gottlieb, E.

PY - 2005

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AB - 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-α prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1α. These results suggest a mechanistic link between SDH mutations and HIF-1α induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.

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KW - prolylhydroxylase

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