Immunophilin-ligands FK506 and CsA inhibit HIF1alpha expression by a VHL- and ubiquitin-independent mechanism.
Hypoxia inducible factor-1alpha (HIF1alpha) plays a key role in the regulation of genes controlling oxygen supply, glucose metabolism and angiogenesis. Its expression in tumors appears to confer an adaptive advantage to their hypoxic microenvironment. We have evaluated the effect of the immunophilin ligands FK506 and cyclosporin A on HIF1alpha levels in different tumor cell lines. Our results indicate that both drugs are potent suppressors of HIF1alpha expression by accelerating the proteasomal degradation of the protein. Unexpectedly, the suppressive effect of these compounds was found to be independent of the presence of von Hippel Lindau factor and the degree of hydroxylation of the HIF1alpha protein. Moreover, HIF1alpha degradation induced by these compounds did not required ubiquitination, as it was also induced in E1 ligase-incompetent cells.
Kong
Xianguo
X
Cardeza Foundation for Hematologic Research and Department of Medicine, Thomas Jefferson University, 1015 Walnut St. Room 807, Philadelphia, PA 19107, USA.
Lin
Zhao
Z
Caro
Jaime
J
D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D025801:Ubiquitin / Q000502:physiology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007166:Immunosuppressive Agents; D025801:Ubiquitin; D016572:Cyclosporine; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D046988:Proteasome Endopeptidase Complex; C497446:VHL protein, human; D016559:Tacrolimus