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

Selak, M., Armour, S., MacKenzie, E., Boulahbel, H., Watson, D., Mansfield, K., Pan, Y., Simon, M., Thompson, C. and Gottlieb, E. (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell, 7(1), pp. 77-85. (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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Boulahbel, Miss Houda and Selak, Dr Mary and Gottlieb, Professor Eyal and MacKenzie, Mrs Elaine
• Authors: Selak, M., Armour, S., MacKenzie, E., Boulahbel, H., Watson, D., Mansfield, K., Pan, Y., Simon, M., Thompson, C., and Gottlieb, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Cell
• ISSN: 1535-6108