Montelukast inhibits hypoxia inducible factor-1α translation in prostate cancer cells. Issue 8 (3rd August 2018)

• Record Type: Journal Article
• Authors: Tang, Caixia; Lei, Hu; Zhang, Jinfu; Liu, Meng; Jin, Jin; Luo, Hao; Xu, Hanzhang; Wu, Yingli
• Is Part Of: Cancer biology & therapy. Volume 19:Issue 8(2018)
• Page Start: 715
• Page End: 721
• Publication Date: 2018-08-03
• Subjects: Montelukast -- HIF-1α -- eIF-2α -- PERK -- Translation; 616.99406
• DOI: 10.1080/15384047.2018.1451279
• Languages: English
• ISSNs: 1538-4047

Abstract

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.