Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis.
Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis.
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DOI：
10.18632/oncotarget.5811
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发表时间：
2015-12-15
期刊：
影响因子：
--
通讯作者：
Tseng CP
中科院分区：
文献类型：
--
作者：
Chang YW;Hsieh PW;Chang YT;Lu MH;Huang TF;Chong KY;Liao HR;Cheng JC;Tseng CP
Podoplanin（PDPN）通过激活血小板C型凝集素样受体2（CLEC-2）引起肿瘤细胞诱导的血小板聚集（TCIPA）来增强肿瘤转移。合成了一种新的无细胞毒性的5-硝基苯甲酸酯化合物2CP，其特异性抑制PDPN/CLEC-2相互作用和TCIPA，而对其他血小板激动剂刺激的血小板聚集没有影响。2CP在体内具有抗肿瘤转移活性，并在实验动物模型中增强顺铂的治疗效果，而不引起出血风险。对2CP分子作用的分析进一步揭示了Akt 1/PDK 1和PKCμ是介导PDPN诱导的血小板活化的两条交替的CLEC-2信号通路。2CP直接与CLEC-2结合，并通过与CLEC-2中PDPN的相同结合口袋竞争，抑制PDPN介导的血小板活化。这项研究提供了证据表明，2CP是第一个确定的血小板拮抗剂与CLEC-2结合活性。2CP增强顺铂的治疗效果表明，化疗剂和具有抗TCIPA活性的药物如2CP的组合可以证明临床有效。
Podoplanin (PDPN) enhances tumor metastases by eliciting tumor cell-induced platelet aggregation (TCIPA) through activation of platelet C-type lectin-like receptor 2 (CLEC-2). A novel and non-cytotoxic 5-nitrobenzoate compound 2CP was synthesized that specifically inhibited the PDPN/CLEC-2 interaction and TCIPA with no effect on platelet aggregation stimulated by other platelet agonists. 2CP possessed anti-cancer metastatic activity in vivo and augmented the therapeutic efficacy of cisplatin in the experimental animal model without causing a bleeding risk. Analysis of the molecular action of 2CP further revealed that Akt1/PDK1 and PKCμ were two alternative CLEC-2 signaling pathways mediating PDPN-induced platelet activation. 2CP directly bound to CLEC-2 and, by competing with the same binding pocket of PDPN in CLEC-2, inhibited PDPN-mediated platelet activation. This study provides evidence that 2CP is the first defined platelet antagonist with CLEC-2 binding activity. The augmentation in the therapeutic efficacy of cisplatin by 2CP suggests that a combination of a chemotherapeutic agent and a drug with anti-TCIPA activity such as 2CP may prove clinically effective.