title: A chemical genomics screen highlights the essential role of mitochondria in HIF-1 regulation.
abstract: Hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development and progression by regulating genes that are vital for proliferation, glycolysis, angiogenesis, and metastasis. To identify strategies of targeting the HIF-1 pathway, we screened a siRNA library against the entire druggable genome and a small-molecule library consisting of 691,200 compounds using a HIF-1 reporter cell line. Although the siRNA library screen failed to reveal any druggable targets, the small-molecule library screen identified a class of alkyliminophenylacetate compounds that inhibit hypoxia-induced HIF-1 reporter activity at single-digit nanomolar concentrations. These compounds were found to inhibit hypoxia but not deferoxamine-induced HIF-1alpha protein stabilization. Further analysis indicated that the alkyliminophenylacetate compounds likely inhibit the HIF-1 pathway through blocking the hypoxia-induced mitochondrial reactive oxygen species (ROS) production. Strikingly, all of the nonalkyliminophenylacetate HIF-1 inhibitors identified from the small-molecule library screen were also found to target mitochondria like the alkyliminophenylacetate compounds. The exclusive enrichment of mitochondria inhibitors from a library of >600,000 diverse compounds by using the HIF-1 reporter assay highlights the essential role of mitochondria in HIF-1 regulation. These results also suggest that targeting mitochondrial ROS production might be a highly effective way of blocking HIF-1 activity in tumors.
authors.affiliation: Cancer Research and Advanced Technology, Global Pharmaceutical Research and Development, AP10, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Lin
authors.forename: Caroline A
authors.initials: CA
authors.lastname: David
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Donnelly
authors.forename: Mike
authors.initials: M
authors.lastname: Michaelides
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Huang
authors.forename: Usha
authors.initials: U
authors.lastname: Warrior
authors.forename: Frank
authors.initials: F
authors.lastname: Weinberg
authors.forename: Kathryn V
authors.initials: KV
authors.lastname: Tormos
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000085:Acetates / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015723:Gene Library; D023281:Genomics / Q000379:methods*; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000737:chemistry; D010597:Pharmacogenetics / Q000379:methods; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D000085:Acetates; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries