Inhibitory effects of polypeptides derived from a snake venom C-type lectin, aggretin, on tumor cell-induced platelet aggregation
Journal
Journal of Thrombosis and Haemostasis
Journal Volume
12
Journal Issue
4
Pages
540-549
Date Issued
2014
Author(s)
Abstract
Summary: Background and objectives: Podoplanin, a transmembrane sialoglycoprotein, is expressed by lymphatic endothelial cells and many tumor cells, and is involved in tumor cell-induced platelet aggregation and tumor metastasis. A recent study found that C-type lectin-like receptor 2 (CLEC-2) is a physiologic receptor for podoplanin. Previous studies showed that aggretin, a snake venom-derived protein, activates platelets by targeting platelet CLEC-2. We hypothesized that the C-terminal fragment of aggretin may bind to platelet CLEC-2 and displace podoplanin, in turn exerting antitumor metastatic effects. Methods and results: Aggretin α-chain C-terminus (residues 106-136; AACT) prolonged the lag phase of platelet aggregation induced by aggretin in human washed platelets, indicating that AACT may target the binding site of CLEC-2. HepG2 cells, which are podoplanin-expressing hepatoma cells, induced platelet aggregation with a lag phase. Pretreatment with AACT inhibited platelet aggregation and prolonged the lag phase induced by HepG2 cells. This inhibitory effect was also found with another hepatocarcinoma cell line, HuH-7. AACT inhibited the interaction between HuH-7 cells and platelets, and a specific binding assay demonstrated that CLEC-2 was the binding site for AACT on platelets. In addition, the invasive ability of HepG2 cells was abolished by AACT in a chick embryo chorioallantoic membrane model. Furthermore, formation of lung metastases after intravenous administration of HuH-7 cells was significantly reduced when mice were treated with AACT. Conclusions: AACT interacts with CLEC-2 of platelets, leading to interference with platelet aggregation and the subsequent metastatic potential of tumor cells. These results suggest that aggretin AACT is a potential candidate for the treatment of tumor metastasis through CLEC-2 blockade. ? 2014 International Society on Thrombosis and Haemostasis.
SDGs
Other Subjects
aggretin alpha chain c terminus; c type lectin like receptor 2; lectin; podoplanin; polypeptide; snake venom; unclassified drug; antineoplastic agent; lectin; membrane protein; PDPN protein, human; peptide; rhodocytin protein, Calloselasma rhodostoma; viper venom; animal cell; animal experiment; article; binding assay; cell strain HepG2; cell strain MCF 7; cell type; chorioallantois; controlled study; hepatoma cell; liver cell carcinoma; lung metastasis; male; mouse; nonhuman; platelet aggregation assay; priority journal; protein expression; thrombocyte aggregation; thrombocyte rich plasma; tumor cell; tumor cell induced platelet aggregation; tumor growth; animal; binding site; cancer transplantation; chemistry; chicken; cytology; drug effects; endothelium cell; HepG2 cell line; human; liver tumor; Lung Neoplasms; MCF 7 cell line; metabolism; metastasis; protein tertiary structure; thrombocyte aggregation; tumor cell line; Animals; Antineoplastic Agents; Binding Sites; Carcinoma, Hepatocellular; Cell Line, Tumor; Chickens; Endothelial Cells; Hep G2 Cells; Humans; Lectins, C-Type; Liver Neoplasms; Lung Neoplasms; MCF-7 Cells; Membrane Glycoproteins; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Peptides; Platelet Aggregation; Protein Structure, Tertiary; Viper Venoms
Type
journal article