Green tea polyphenol epigallocatechin-3-gallate inhibits thrombin-induced hepatocellular carcinoma cell invasion and p42/p44-MAPKinase activation.
Thrombin has been recently demonstrated to promote hepatocellular carcinoma (HCC) cell migration by activation of the proteinase-activated receptor (PAR) subtypes PAR1 and PAR4 suggesting a role of these proteinase-receptor systems in HCC progression. In this study, we investigated the effect of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic compound of green tea on thrombin-PAR1/PAR4-mediated hepatocellular carcinoma cell invasion and p42/p44 MAPKinase activation. In this study we used the permanent liver carcinoma cell line HEP-3B and two primary cultures established from surgically resected HCCs. We found that stimulation of HCC cells with thrombin, the PAR1-selective activating peptide, TFLLRN-NH2, and the PAR4-selective activating peptide, AYPGKF-NH2, increased cell invasion across a Matrigel-coated membrane barrier and stimulated activation of p42/p44 MAPKinase phosphorylation. Both the effects on p42/p44 MAPKinases, and on cell invasiveness induced by thrombin and the PAR1/4 subtype-selective agonist peptides were effectively blocked by EGCG. The results clearly identify EGCG as a potent inhibitor of the thrombin-PAR1/PAR4-p42/p44 MAPKinase invasive signaling axis in hepatocellular carcinoma cells as a previously unrecognized mode of action for EGCG in cancer cells. Moreover, the results suggest that (-)-epigal-locatechin-3-gallate might have therapeutic potential for hepatocellular carcinoma.
Department of General, Visceral and Vascular Surgery, Research Center Lobeda, Medical Faculty at the Friedrich Schiller University Jena, D-07747 Jena, Germany. roland.kaufmann@med.uni-jena.de
Roland
R
Kaufmann
Peter
P
Henklein
Petra
P
Henklein
Utz
U
Settmacher
D016588:Anticarcinogenic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D044463:Receptor, PAR-1 / Q000819:agonists / Q000378:metabolism; D018179:Receptors, Thrombin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013662:Tea / Q000737:chemistry; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors
C482003:AYPGKG-NH(2); D016588:Anticarcinogenic Agents; D009842:Oligopeptides; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; C483910:TFLLRNPNDK-NH2; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013917:Thrombin; C112908:protease-activated receptor 4; D010975:Platelet Aggregation Inhibitors