A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells.
A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells.
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DOI：
10.18632/oncotarget.6990
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发表时间：
2016-02-23
期刊：
影响因子：
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通讯作者：
Chen ZN
中科院分区：
文献类型：
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作者：
Fu ZG;Wang L;Cui HY;Peng JL;Wang SJ;Geng JJ;Liu JD;Feng F;Song F;Li L;Zhu P;Jiang JL;Chen ZN
CD147是一种I型跨膜糖蛋白，在多种肿瘤类型中均有高表达，在肿瘤进展中发挥重要作用，特别是通过促进肝细胞癌细胞的运动和侵袭。这些关键作用使CD147成为肝癌治疗干预的一个有吸引力的靶点，但到目前为止还没有开发出CD147的小分子抑制剂。为了确定候选抑制剂，我们使用了来自CD147结构的药效团模型来虚拟筛选超过300,000种化合物。对排名最高的100种化合物进行了生物测试，其中最有效的一种，被称为AC-73(ID号：AN-465/42834501)，得到了进一步的研究。我们证实了AC-73靶向CD147，并进一步证明它可以特异性地干扰CD147的二聚化。此外，分子对接和诱变实验表明，AC-73与CD147的可能结合部位包括位于CD147 N端的Glu64和Glu73，这两个残基位于CD147的二聚体界面。功能分析显示，AC-73抑制了典型肝癌细胞的运动和侵袭，但不抑制缺乏CD147基因的肝癌细胞，显示了靶向作用。此外，AC-73通过下调CD147/ERK1/2/信号转导和转录激活因子3(STAT3)信号通路，抑制基质金属蛋白酶-2，从而减少肝细胞癌的转移。最后，AC-73抑制了裸鼠原位肝转移模型的进展，提示AC-73或其衍生物有可能用于肝细胞癌的干预。我们的结论是，新型小分子抑制剂AC-73可能通过破坏CD147的二聚化，从而主要抑制对肿瘤进展至关重要的CD147/ERK1/2/STAT3/MMP2通路，从而抑制肝癌的迁移和侵袭。
CD147, a type I transmembrane glycoprotein, is highly expressed in various cancer types and plays important roles in tumor progression, especially by promoting the motility and invasion of hepatocellular carcinoma (HCC) cells. These crucial roles make CD147 an attractive target for therapeutic intervention in HCC, but no small-molecule inhibitors of CD147 have been developed to date. To identify a candidate inhibitor, we used a pharmacophore model derived from the structure of CD147 to virtually screen over 300,000 compounds. The 100 highest-ranked compounds were subjected to biological assays, and the most potent one, dubbed AC-73 (ID number: AN-465/42834501), was studied further. We confirmed that AC-73 targeted CD147 and further demonstrated it can specifically disrupt CD147 dimerization. Moreover, molecular docking and mutagenesis experiments showed that the possible binding sites of AC-73 on CD147 included Glu64 and Glu73 in the N-terminal IgC2 domain, which two residues are located in the dimer interface of CD147. Functional assays revealed that AC-73 inhibited the motility and invasion of typical HCC cells, but not HCC cells that lacked the CD147 gene, demonstrating on-target action. Further, AC-73 reduced HCC metastasis by suppressing matrix metalloproteinase (MMP)-2 via down-regulation of the CD147/ERK1/2/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, AC-73 attenuated progression in an orthotopic nude mouse model of liver metastasis, suggesting that AC-73 or its derivatives have potential for use in HCC intervention. We conclude that the novel small-molecule inhibitor AC-73 inhibits HCC mobility and invasion, probably by disrupting CD147 dimerization and thereby mainly suppressing the CD147/ERK1/2/STAT3/MMP-2 pathways, which are crucial for cancer progression.