Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α
Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α
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DOI：
10.1158/1535-7163.mct-07-0463
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发表时间：
2008-01-01
影响因子：
5.7
通讯作者：
Powis, Garth
中科院分区：
文献类型：
--
作者：
Koh, Mei Y.;Spivak-Kroizman, Taly;Powis, Garth
我们之前报道过PX-478 （s -2-氨基-3-[4'-N，N，-双（氯乙基）氨基]苯基丙酸N-氧化物二盐酸盐）对多种人类肿瘤异种移植物具有有效的抗肿瘤活性，其抗肿瘤活性与肿瘤内缺氧诱导因子-1 α (HIF-1 α)的水平有关。我们现在报道，PX-478在多种癌细胞系中抑制HIF-1 α蛋白水平和转激活。低氧诱导的血管内皮生长因子形成被PX-478抑制，而正常氧下血管内皮生长因子的基线水平不受影响。对PX-478作用机制的研究表明，HIF-1 α抑制在常氧和缺氧情况下都发生，不需要pVHL或p53。此外，通过S-35标记实验和利用HIF-1 α的5'非翻译区进行的报告基因分析发现，PX-478可以降低HIF-1 α mRNA的水平并抑制翻译。此外，在较小程度上，PX-478还抑制HIF-1 α去泛素化，导致HIF-1 α多泛素化水平升高。PX-478对HIF-1 α水平的抑制作用主要是由于其抑制翻译，因为HIF-1 α在缺氧时继续翻译，而大多数蛋白质的翻译减少。我们得出结论，PX-478在多个水平上抑制HIF-1 α，这些水平共同或单独可能有助于其对表达HIF-1 α的肿瘤的抗肿瘤活性。
We have reported previously that PX-478 (S-2-amino-3-[4'-N,N,-bis(chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) has potent antitumor activity against a variety of human tumor xenografts associated with the levels of the hypoxia-inducible factor-1 alpha (HIF-1 alpha) within the tumor. We now report that PX-478 inhibits HIF-1 alpha protein levels and transactivation in a variety of cancer cell lines. Hypoxia-induced vascular endothelial growth factor formation was inhibited by PX-478, whereas baseline levels of vascular endothelial growth factor in normoxia were unaffected. Studies of the mechanism of PX-478 action showed that HIF-1 alpha inhibition occurs in both normoxia and hypoxia and does not require pVHL or p53. In addition, PX-478 decreases levels of HIF-1 alpha mRNA and inhibits translation as determined by S-35 labeling experiments and reporter assays using the 5' untranslated region of HIF-1 alpha. Moreover, to a lesser extent, PX-478 also inhibits HIF-1 alpha deubiquitination resulting in increased levels of polyubiquitinated HIF-1 alpha. The inhibitory effect of PX-478 on HIF-1 alpha levels is primarily due to its inhibition of translation because HIF-1 alpha translation continues in hypoxia when translation of most proteins is decreased. We conclude that PX-478 inhibits HIF-1 alpha at multiple levels that together or individually may contribute to its antitumor activity against HIF-1 alpha-expressing tumors.