Q39, a quinoxaline 1,4-Di-N-oxide derivative, inhibits hypoxia-inducible factor-1α expression and the Akt/mTOR/4E-BP1 signaling pathway in human hepatoma cells
Q39, a quinoxaline 1,4-Di-N-oxide derivative, inhibits hypoxia-inducible factor-1α expression and the Akt/mTOR/4E-BP1 signaling pathway in human hepatoma cells
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DOI：
10.1007/s10637-010-9462-y
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发表时间：
2011-12-01
影响因子：
3.4
通讯作者：
Yang, Bo
中科院分区：
文献类型：
--
作者：
Weng, Qinjie;Zhang, Jun;Yang, Bo
大量研究表明，缺氧诱导因子-1 α（HIF-1 α）及其下游靶点血管内皮生长因子（VEGF）在肝细胞癌血管生成、侵袭和转移中起重要作用。3-（4-溴苯基）-2-（乙磺酰基）-6-甲基喹喔啉1，4-二氧化物（Q39）最近在常氧和缺氧的广泛细胞系中显示出很大的抗增殖活性。在本研究中，Q39在体外和体内均表现出较高的抗肝癌增殖活性，主要通过诱导细胞凋亡。此外，Q39对HIF-1 α的抑制导致VEGF表达急剧下降。这些结果表明Q39是一种有效的HIF-1 α抑制剂，并为其抗癌活性机制提供了新的视角。有趣的是，Q39既不影响HIF-1 α降解速率，也不影响HIF-1 α稳态mRNA水平。相反，Q39对HIF-1 α积累的抑制与mTOR和4 E-BP 1的显著去磷酸化相关，这是一种已知在翻译水平调节蛋白质表达的途径。
Cumulative evidence has established that hypoxia-inducible factor-1 alpha (HIF-1 alpha) and its downstream target, vascular endothelial growth factor (VEGF), play a critical role in hepatocellular carcinoma angiogenesis, invasiveness and metastasis. 3-(4-bromophenyl)-2-(ethylsulfonyl)-6-methylquinoxaline 1,4-dioxide (Q39) has recently shown great antiproliferative activity in extensive cell lines in normoxia and hypoxia. In this study, Q39 exhibited high antiproliferative activity against hepatoma both in vitro and in vivo, mainly by inducing apoptosis. In addition, suppression of HIF-1 alpha by Q39 resulted in a drastic decrease in VEGF expression. These results indicate that Q39 is an effective inhibitor of HIF-1 alpha and provide new perspectives into the mechanism of its anticancer activity. Interestingly, neither the HIF-1 alpha degradation rate nor the HIF-1 alpha steady-state mRNA level was affected by Q39. Instead, suppression of HIF-1 alpha accumulation by Q39 correlated with prominent dephosphorylation of mTOR and 4E-BP1, a pathway known to regulate protein expression at the translational level.