Montelukast inhibits hypoxia inducible factor-1α translation in prostate cancer cells

Cancer Biol Ther. 2018 Aug 3;19(8):715-721. doi: 10.1080/15384047.2018.1451279. Epub 2018 May 8.

Abstract

Through regulating the expression of hundreds of genes, hypoxia-inducible factor -1(HIF-1) plays a critical role in hypoxic adaption of cancer cells and is considered as a target for cancer therapy. Here we show that montelukast, a clinical leukotriene receptor antagonist for the treatment of asthma, inhibits hypoxia or CoCl2-induced HIF-1α activation and reduces its protein expression in prostate cancer cells. However, the other two leukotriene receptor antagonists, pranlukast and zafirlukast, cannot decrease HIF-1α protein, which indicates that montelukast-induced downregulation of HIF-1α is not mediated by leukotriene receptor. Neither proteasome inhibitor MG132 nor the lysosomal inhibitor chloroquine (CQ) can block montelukast-induced downregulation of HIF-1α protein. Interestingly, GSK2606414, a PKR-like endoplasmic reticulum kinase (PERK) inhibitor, abrogates montelukast-induced downregulation of HIF-1α under hypoxic conditions. However, montelukast increases phosphorylation of eIF-2α at Ser51. Moreover, montelukast inhibits the proliferation of prostate cancer cells, which can be reversed by overexpression of HIF-1α protein. In conclusion, we identify montelukast may be used as a novel agent for the treatment of prostate cancer by decreasing HIF-1α protein translation.

Keywords: HIF-1α; Montelukast; PERK; Translation; eIF-2α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclopropanes
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, Reporter
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Male
  • Prostatic Neoplasms / genetics*
  • Protein Biosynthesis / drug effects*
  • Proteolysis
  • Quinolines / pharmacology*
  • Receptors, Leukotriene / metabolism
  • Sulfides

Substances

  • Acetates
  • Cyclopropanes
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Quinolines
  • Receptors, Leukotriene
  • Sulfides
  • montelukast

Grant support

This work was supported in part by grants from the National Key Research and Development Program of China (No. 2017YFA0505200), National Natural Science Foundation of China (81570118, 81700475), Science and Technology Committee of Shanghai (15401901800), Innovation Program of Shanghai Municipal Education Commission (13YZ028).