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

Mary A Selak; Sean M Armour; Elaine D MacKenzie; Houda Boulahbel; David G Watson; Kyle D Mansfield; Yi Pan; M Celeste Simon; Craig B Thompson; Eyal Gottlieb

doi:10.1016/j.ccr.2004.11.022

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

Cancer Cell. 2005 Jan;7(1):77-85. doi: 10.1016/j.ccr.2004.11.022.

Authors

Mary A Selak¹, Sean M Armour, Elaine D MacKenzie, Houda Boulahbel, David G Watson, Kyle D Mansfield, Yi Pan, M Celeste Simon, Craig B Thompson, Eyal Gottlieb

Affiliation

¹ Apoptosis and Tumour Physiology Laboratory, Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Switchback Road, Glasgow G61 1BD, United Kingdom.

PMID: 15652751
DOI: 10.1016/j.ccr.2004.11.022

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-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.

MeSH terms

Animals
Cell Line
Cell Transformation, Neoplastic
Citric Acid Cycle / physiology*
Enzyme Activation
Gene Expression Regulation, Enzymologic
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Mitochondria / metabolism
Oncogenes*
Procollagen-Proline Dioxygenase / antagonists & inhibitors
Procollagen-Proline Dioxygenase / genetics
Procollagen-Proline Dioxygenase / metabolism*
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Reactive Oxygen Species / metabolism
Signal Transduction / physiology
Succinate Dehydrogenase / antagonists & inhibitors
Succinate Dehydrogenase / genetics
Succinate Dehydrogenase / metabolism
Succinic Acid / metabolism*
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Von Hippel-Lindau Tumor Suppressor Protein

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
RNA, Small Interfering
Reactive Oxygen Species
Transcription Factors
Tumor Suppressor Proteins
Succinic Acid
Procollagen-Proline Dioxygenase
Succinate Dehydrogenase
Ubiquitin-Protein Ligases
Von Hippel-Lindau Tumor Suppressor Protein
VHL protein, human