Doxycycline directly targets PAR1 to suppress tumor progression.
Doxycycline directly targets PAR1 to suppress tumor progression.
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强力霉素直接靶向 PAR1 抑制肿瘤进展
DOI：
10.18632/oncotarget.15166
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发表时间：
2017-03-07
期刊：
影响因子：
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通讯作者：
Yang C
中科院分区：
文献类型：
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作者：
Zhong W;Chen S;Zhang Q;Xiao T;Qin Y;Gu J;Sun B;Liu Y;Jing X;Hu X;Zhang P;Zhou H;Sun T;Yang C
多西环素已被报道具有抗癌活性，并已被临床试验评估为抗癌药物。然而，多西环素在癌细胞中的直接靶点仍不清楚。在这项研究中，我们使用化学蛋白质组学的方法来确定蛋白酶激活的受体1(PAR1)是多西环素抑制的特异性靶点。结合实验和单分子成像实验证实多西环素对PAR1的抑制作用。基于PAR1/凝血酶模型评估多西环素对多组学和细胞功能的影响。分子对接和分子动力学模拟表明多西环素与PAR1中的关键氨基酸相互作用。PAR1的突变进一步证实了基于计算的结果。此外，多西环素在体外和体内对肿瘤中的PAR1信号具有高度的选择性抑制作用。用多西环素和PAR1共染色的病理标本，发现多西环素荧光强度与PAR1表达呈明显正相关。因此，多西环素可能是一种有用的靶向抗癌药物，应在临床试验中进一步研究。
Doxycycline have been reported to exert anti-cancer activity and have been assessed as anti-cancer agents in clinical trials. However, the direct targets of doxycycline in cancer cells remain unclear. In this study, we used a chemical proteomics approach to identify the Protease-activated receptor 1 (PAR1) as a specific target of inhibition of doxycycline. Binding assays and single-molecule imaging assays were performed to confirm the inhibition of doxycycline to PAR1. The effect of doxycycline on multi-omics and cell functions were assessed based on a PAR1/thrombin model. Molecular docking and molecular dynamic simulations revealed that doxycycline interacts with key amino acids in PAR1. Mutation of PAR1 further confirmed the computation-based results. Moreover, doxycycline provides highly selective inhibition of PAR1 signaling in tumors in vitro and in vivo. Using pathological clinical samples co-stained for doxycycline and PAR1, it was found that doxycycline fluorescence intensity and PAR1 expression shown a clear positive correlation. Thus, doxycycline may be a useful targeted anti-cancer drug that should be further investigated in clinical trials.