Identification of a novel small molecule HIF-1alpha translation inhibitor.
OBJECTIVE
Hypoxia inducible factor-1 (HIF-1), the central mediator of the cellular response to low oxygen, functions as a transcription factor for a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1 is overexpressed in cancer and has become an important therapeutic target in solid tumors. In this study, a novel HIF-1alpha inhibitor was identified and its molecular mechanism was investigated.


METHODS
Using a HIF-responsive reporter cell-based assay, a 10,000-member natural product-like chemical compound library was screened to identify novel HIF-1 inhibitors. This led us to discover KC7F2, a lead compound with a central structure of cystamine. The effects of KC7F2 on HIF-1 transcription, translation, and protein degradation processes were analyzed.


RESULTS
KC7F2 markedly inhibited HIF-mediated transcription in cells derived from different tumor types, including glioma, breast, and prostate cancers, and exhibited enhanced cytotoxicity under hypoxia. KC7F2 prevented the activation of HIF-target genes such as carbonic anhydrase IX, matrix metalloproteinase 2 (MMP2), endothelin 1, and enolase 1. An investigation into the mechanism of action of KC7F2 showed that it worked through the down-regulation of HIF-1alpha protein synthesis, an effect accompanied by the suppression of the phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 and p70 S6 kinase, key regulators of HIF-1alpha protein synthesis.


CONCLUSIONS
These results show that KC7F2 is a potent HIF-1 pathway inhibitor and its potential as a cancer therapy agent warrants further study.
Narita
Takuhito
T
Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Yin
Shaoman
S
Gelin
Christine F
CF
Moreno
Carlos S
CS
Yepes
Manuel
M
Nicolaou
K C
KC
Van Meir
Erwin G
EG
D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000494:pharmacology / Q000627:therapeutic use*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004220:Disulfides / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010100:Oxygen / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D054852:Small Molecule Libraries / Q000032:analysis; D013449:Sulfonamides / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004220:Disulfides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C545729:KC7F2 compound; D054852:Small Molecule Libraries; D013449:Sulfonamides; D010100:Oxygen