Cellular Sensing System for Green Tea Polyphenol Epigallocatechin Gallate

Abstract

The green tea catechin (‐)-epigallocatechin-3-O-gallate (EGCG) is known to exhibit various biological and pharmacological properties. We have identified 67-kDa laminin receptor (67LR) as a cell-surface EGCG receptor that confers EGCG responsiveness to many cancer cells at physiological concentrations. Here we provide an overview of several pathways that sense and manage the activities of EGCG. EGCG has been shown to rescue mice from lipopolysaccharide (LPS)-induced lethal endotoxemia and downregulate inflammatory responses in macrophages. LPS is one of the most powerful activators of toll-like receptor (TLR)4 signaling and is also well known to induce production of inflammatory mediators. A negative regulator of TLR signaling, Toll-interacting protein (Tollip), is indispensable for mediating the anti-inflammatory action of EGCG, and its protein expression level is upregulated by EGCG through 67LR. Additionally, EGCG can reduce the expression of TLR4 via 67LR. Using a direct genetic screen, eukaryotic translation elongation factor 1A (eEF1A) is identified as a component responsible for the anti-melanoma activity of EGCG. EGCG induces the dephosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) at Thr-696 and activates myosin phosphatase through both eEF1A and 67LR. Silencing of 67LR, eEF1A, or MYPT1 in tumor cells results in abrogation of EGCG-induced tumor growth inhibition in vivo. Additionally, we found that eEF1A is up-regulated by EGCG through 67LR. EGCG has been shown to be able to induce apoptotic cell death in multiple myeloma cells through the 67LR, while having no significant effect on peripheral blood mononuclear cells (PBMCs). The expression of 67LR was significantly elevated in myeloma cells compared to PBMCs. We found that the apoptosis-inducing activity of EGCG in multiple myeloma cells is attributable to the activation of acid sphingomyelinase (ASM) that hydrolyzes sphingomyelin into ceramide. EGCG induces ASM translocation to the plasma membrane and protein kinase C delta (PKCδ) phosphorylation at Ser 664 , which was necessary for ASM/ceramide signaling, via 67LR. Furthermore, EGCG activates PKCδ/ASM/ceramide pathway by activating Akt/eNOS/NO/cGMP signaling through 67LR. We also found that the upregulation of cGMP is a rate-determining process of this cell death pathway, and cancer-overexpressed negative regulator of cGMP, PDE5 attenuates the cell death induced by EGCG. Vardenafil, one of the PDE5 selective inhibitors used for treating erectile dysfunction potentiates the anti-cancer effect of EGCG. These results demonstrate that cGMP elevation caused by targeting the overexpressed 67LR and PDE5 in cancer cells may be a useful approach for cancer-specific chemotherapy.