Montelukast inhibits hypoxia inducible factor-1α translation in prostate cancer cells
Montelukast inhibits hypoxia inducible factor-1α translation in prostate cancer cells
复制标题
Montelukast 抑制前列腺癌细胞中缺氧诱导因子 1α 的翻译。
DOI：
10.1080/15384047.2018.1451279
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发表时间：
2018-01-01
影响因子：
3.6
通讯作者：
Wu, Yingli
中科院分区：
文献类型：
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作者：
Tang, Caixia;Lei, Hu;Wu, Yingli
缺氧诱导因子-1（hypoxia-inducible factor -1, HIF-1）通过调控数百个基因的表达，在癌细胞的缺氧适应中起着至关重要的作用，被认为是癌症治疗的靶点。本研究表明，孟鲁司特是一种用于治疗哮喘的临床白三烯受体拮抗剂，可抑制缺氧或cocl2诱导的HIF-1 α活化，并降低其在前列腺癌细胞中的蛋白表达。而另外两种白三烯受体拮抗剂普鲁司特和扎非鲁司特不能降低HIF-1 α蛋白，这表明孟鲁司特诱导的HIF-1 α下调不是由白三烯受体介导的。蛋白酶体抑制剂MG132和溶酶体抑制剂氯喹（CQ）都不能阻断孟鲁司特诱导的HIF-1 α蛋白下调。有趣的是，GSK2606414，一种pkr样内质网激酶（PERK）抑制剂，在缺氧条件下消除孟鲁司特诱导的HIF-1 α下调。然而，孟鲁司特增加了eIF-2 α在Ser51位点的磷酸化。此外，孟鲁司特抑制前列腺癌细胞的增殖，这可以通过过度表达HIF-1 α蛋白来逆转。总之，我们确定孟鲁司特可能通过降低HIF-1 α蛋白的翻译而被用作治疗前列腺癌的新型药物。
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-1 alpha activation and reduces its protein expression in prostate cancer cells. However, the other two leukotriene receptor antagonists, pranlukast and zafirlukast, cannot decrease HIF-1 alpha protein, which indicates that montelukast-induced downregulation of HIF-1 alpha is not mediated by leukotriene receptor. Neither proteasome inhibitor MG132 nor the lysosomal inhibitor chloroquine (CQ) can block montelukast-induced downregulation of HIF-1 alpha protein. Interestingly, GSK2606414, a PKR-like endoplasmic reticulum kinase (PERK) inhibitor, abrogates montelukast-induced downregulation of HIF-1 alpha under hypoxic conditions. However, montelukast increases phosphorylation of eIF-2 alpha at Ser51. Moreover, montelukast inhibits the proliferation of prostate cancer cells, which can be reversed by overexpression of HIF-1 alpha protein. In conclusion, we identify montelukast may be used as a novel agent for the treatment of prostate cancer by decreasing HIF-1 alpha protein translation.