Green tea polyphenol epigallocatechin-3-gallate inhibits thrombin-induced hepatocellular carcinoma cell invasion and p42/p44-MAPKinase activation

Abstract

Abstract.Thrombin has been recently demonstrated to promote hepatocellular carcinoma (HCC) cell migration by activation of the proteinase-activated receptor (PAR) subtypes PAR 1 and PAR 4 suggesting a role of these proteinasereceptor 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-PAR 1 /PAR 4 -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 PAR 1 -selective activating peptide, TFLLRN-NH 2 , and the PAR 4 -selective activating peptide, AYPGKF-NH 2 , 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 PAR 1/4 subtype-selective agonist peptides were effectively blocked by EGCG. The results clearly identify EGCG as a potent inhibitor of the thrombin-PAR 1 /PAR 4 -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.

Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway

“…Representative results of at least three independent experiments are shown. the thrombin-PAR1/PAR4-p42/p44 MAPKinase invasive signaling axis in hepatocellular carcinoma cells (30). HIF-1α/ VEGF function was also a therapeutic target for EGCG in cancer chemoprevention and anticancer therapy (15,22).…”

Flavonoids, a ubiquitous dietary phenolic subclass, exert extensive in vitro anti-invasive and in vivo anti-metastatic activities

“…According to the published literature, EGCG, EGC, ECG, and EC are the most studied compounds in this field so far. In hepatoma, EGCG blocked the thrombin-induced invasion of Hep3B cells by suppressing p42/p44 MAP kinase (ERK1/2) activation [79] and significantly inhibited HepG2 cell invasion into basement membranes by reducing the expression of the MUC1, MMP-2, and MMP-9 proteins [80]. EGCG also inhibited the invasion and migration of SK-Hep-1 cells and rat hepatic stellate cells (HSCs) by suppressing MMP-2/MMP-9 and decreasing MMP-2 and MT1-MMP, respectively [81,82].…”

Protease-activated receptors in cancer: A systematic review

“…The expression of PAR1 has been correlated with the malignant phenotype. For PAR1, a role in the progression of epithelial tumors, including breast (75,82,94,97,98), colon (76,99), kidney (100), pulmonary tumor (101), melanoma (102) and hepatocellular carcinoma (80,103) has been shown.…”