title: Translational suppression of HIF-1α by miconazole through the mTOR signaling pathway.
abstract: BACKGROUND
  Miconazole is an imidazole antifungal agent that has amply been used in the treatment of superficial mycosis. Preliminary data indicate that miconazole may also induce anticancer effects. As yet, however, little is known about the therapeutic efficacy of miconazole on cancer and the putative mechanism(s) involved. Here, we show that miconazole suppresses hypoxia inducible factor-1α (HIF-1α) protein translation in different cancer-derived cells.
  
  
  METHODS
  The effect of miconazole on HIF-1α expression was examined by Western blotting and reverse transcriptase polymerase chain reaction assays in human U87MG and MCF-7 glioma and breast cancer-derived cell lines, respectively. The transcriptional activity of the HIF-1 complex was confirmed using a luciferase assay. To assess whether angiogenic factors are increased under hypoxic conditions in these cells, vascular endothelial growth factor (VEGF) levels were measured by ELISA. Metabolic labeling was performed to examine HIF-1α protein translation and global protein synthesis. The role of the mammalian target of rapamycin (mTOR) signaling pathway was examined to determine translation regulation of HIF-1α after miconazole treatment.
  
  
  RESULTS
  Miconazole was found to suppress HIF-1α protein expression through post-transcriptional regulation in U87MG and MCF-7 cells. The suppressive effect of HIF-1α protein synthesis was found to be due to inhibition of mTOR. Miconazole significantly inhibited the transcriptional activity of the HIF-1 complex and the expression of its target VEGF. Moreover, miconazole was found to suppress global protein synthesis by inducing phosphorylation of the translation initiation factor 2α (eIF2α).
  
  
  CONCLUSIONS
  Our data indicate that miconazole plays a role in translational suppression of HIF-1α. We suggest that miconazole may represent a novel therapeutic option for the treatment of cancer.
authors: Department of Microbiology, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu, 704-701, Republic of Korea.
authors: Jee-Young
authors: JY
authors: Park
authors: Hui-Jung
authors: HJ
authors: Jung
authors: Incheol
authors: I
authors: Seo
authors: Bijay Kumar
authors: BK
authors: Jha
authors: Seong-Il
authors: SI
authors: Suh
authors: Min-Ho
authors: MH
authors: Suh
authors: Won-Ki
authors: WK
authors: Baek
mesh_terms: D045744:Cell Line, Tumor; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D061986:MCF-7 Cells; D008825:Miconazole / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D008825:Miconazole; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases