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.

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