Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis
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Yao-Wen Chang1,*, Pei-Wen Hsieh1,2,*, Yu-Tsui Chang3, Meng-Hong Lu3, Tur-Fu Huang4, Kowit-Yu Chong1,3,5, Hsiang-Ruei Liao1,2, Ju-Chien Cheng6, Ching-Ping Tseng1,3,5,7
1Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC)
2Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC)
3Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC)
4Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei 104, Taiwan, Republic of China (ROC)
5Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan, Republic of China (ROC)
6Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan, Republic of China (ROC)
7Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, Republic of China (ROC)
*These authors have contributed equally to this work and both of them are first authors
Ching-Ping Tseng, e-mail: [email protected]
Keywords: TCIPA, podoplanin, platelet aggregation, tumor metastasis
Received: June 03, 2015 Accepted: October 17, 2015 Published: October 30, 2015
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.
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