Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells.
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 HIF1alpha stabilization by succinate or fumarate, respectively, either of which, when in excess, inhibits HIFalpha 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 HIF1alpha levels to SDH-suppressed cells, indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction.
MacKenzie
Elaine D
ED
Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, Scotland G61 1BD, UK.
Selak
Mary A
MA
Tennant
Daniel A
DA
Payne
Lloyd J
LJ
Crosby
Stuart
S
Frederiksen
Casper M
CM
Watson
David G
DG
Gottlieb
Eyal
E
D015687:Cell Hypoxia / Q000187:drug effects*; D002460:Cell Line; D002463:Cell Membrane Permeability; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D013385:Succinate Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D025801:Ubiquitin; D013385:Succinate Dehydrogenase; D046988:Proteasome Endopeptidase Complex