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Molecular and Cellular Biology, May 2007, p. 3282-3289, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.01927-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cell-Permeating {alpha}-Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient Cells{triangledown}

Elaine D. MacKenzie,1,{dagger} Mary A. Selak,1,{dagger} Daniel A. Tennant,1 Lloyd J. Payne,3 Stuart Crosby,3 Casper M. Frederiksen,1,{ddagger} David G. Watson,2 and Eyal Gottlieb1*

Apoptosis and Tumour Physiology Laboratory, Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, United Kingdom,1 Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, United Kingdom,2 Tocris Cookson Ltd, Northpoint, Fourth Way, Avonmouth, Bristol BS11 8TA, United Kingdom3

Received 11 October 2006/ Returned for modification 15 November 2006/ Accepted 10 February 2007

Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are components of the tricarboxylic acid (TCA) cycle and tumor suppressors. Loss of SDH or FH induces pseudohypoxia, a major tumor-supporting event, which is the activation of hypoxia-inducible factor (HIF) under normoxia. In SDH- or FH-deficient cells, HIF activation is due to HIF1{alpha} stabilization by succinate or fumarate, respectively, either of which, when in excess, inhibits HIF{alpha} prolyl hydroxylase (PHD). To reactivate PHD, we focused on its substrate, {alpha}-ketoglutarate. We designed and synthesized cell-permeating {alpha}-ketoglutarate derivatives, which build up rapidly and preferentially in cells with a dysfunctional TCA cycle. This study shows that succinate- or fumarate-mediated inhibition of PHD is competitive and is reversed by pharmacologically elevating intracellular {alpha}-ketoglutarate. Introduction of {alpha}-ketoglutarate derivatives restores normal PHD activity and HIF1{alpha} levels to SDH-suppressed cells, indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction.

* Corresponding author. Mailing address: The Beatson Institute for Cancer Research, Switchback Road, Glasgow, Scotland G61 1BD, United Kingdom. Phone: 44 (0) 141 330 3981. Fax: 44 (0) 141 942 6521. E-mail: e.gottlieb{at}beatson.gla.ac.uk

{triangledown} Published ahead of print on 26 February 2007.

{dagger} E.D.M. and M.A.S. contributed equally to this work.

{ddagger} Present address: Center for Experimental Bioinformatics, University of Southern Denmark, Odense, Denmark.

Molecular and Cellular Biology, May 2007, p. 3282-3289, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.01927-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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