Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis
Journal
Oncotarget
Journal Volume
6
Journal Issue
40
Pages
42733-42748
Date Issued
2015
Author(s)
Chang, Yao-Wen
Hsieh, Pei-Wen
Chang, Yu-Tsui
Lu, Meng-Hong
Chong, Kowit-Yu
Liao, Hsiang-Ruei
Cheng, Ju-Chien
Abstract
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.
SDGs
Other Subjects
2cp; cisplatin; nitrobenzoic acid derivative; phosphoinositide dependent protein kinase 1; podoplanin; protein Akt1; protein CLEC 2; protein kinase C mu; protein kinase Syk; thrombocyte receptor; unclassified drug; antineoplastic agent; antithrombocytic agent; CLEC2B protein, human; lectin; membrane protein; nitrobenzoic acid derivative; PDPN protein, human; animal cell; animal experiment; animal model; antineoplastic activity; Article; controlled study; drug efficacy; drug identification; drug protein binding; drug receptor binding; drug structure; drug synthesis; human; human cell; in vivo study; lung metastasis; metastasis inhibition; mouse; nonhuman; protein synthesis inhibition; rat; signal transduction; structure analysis; thrombocyte aggregation inhibition; animal; Bagg albino mouse; drug effects; drug screening; metabolism; molecular model; nude mouse; pathology; physiology; surface plasmon resonance; thrombocyte; thrombocyte aggregation; tumor invasion; Western blotting; Animals; Antineoplastic Agents; Blood Platelets; Blotting, Western; Humans; Lectins, C-Type; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Molecular; Neoplasm Invasiveness; Nitrobenzoates; Platelet Aggregation; Platelet Aggregation Inhibitors; Surface Plasmon Resonance; Xenograft Model Antitumor Assays
Type
journal article