Identification of a novel small molecule HIF-1α translation inhibitor

Academic Article

Abstract

  • Purpose: 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-1α inhibitor was identified and its molecular mechanism was investigated. Experimental Design: 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-1α protein synthesis, an effect accompanied by the suppression of the phosphorylation of eukaryotic translation initiation factor 4Ebinding protein 1 and p70 S6 kinase, key regulators of HIF-1α protein synthesis. Conclusion: These results show that KC7F2 is a potent HIF-1 pathway inhibitor and its potential as a cancer therapy agent warrants further study. © 2009 American Association for Cancer Research.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Narita T; Yin S; Gelin CF; Moreno CS; Yepes M; Nicolaou KC; Van Meir EG
  • Start Page

  • 6128
  • End Page

  • 6136
  • Volume

  • 15
  • Issue

  • 19