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. 2008 Jun;9(6):1034-1049.
doi: 10.3390/ijms9061034. Epub 2008 Jun 20.

Targeting receptor tyrosine kinases for chemoprevention by green tea catechin, EGCG

Masahito Shimizu  1 , Yohei Shirakami  1 , Hisataka Moriwaki  1
Affiliations

Targeting receptor tyrosine kinases for chemoprevention by green tea catechin, EGCG

Masahito Shimizu et al. Int J Mol Sci. 2008 Jun.

Abstract

Tea is one of the most popular beverages consumed worldwide. Epidemiologic studies show an inverse relationship between consumption of tea, especially green tea, and development of cancers. Numerous in vivo and in vitro studies indicate strong chemopreventive effects for green tea and its constituents against cancers of various organs. (-)-Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, appears to be the most biologically active constituent in tea with respect to inhibiting cell proliferation and inducing apoptosis in cancer cells. Recent studies indicate that the receptor tyrosine kinases (RTKs) are one of the critical targets of EGCG to inhibit cancer cell growth. EGCG inhibits the activation of EGFR (erbB1), HER2 (neu/erbB2) and also HER3 (neu/erbB3), which belong to subclass I of the RTK superfamily, in various types of human cancer cells. The activation of IGF-1 and VEGF receptors, the other members of RTK family, is also inhibited by EGCG. In addition, EGCG alters membrane lipid organization and thus inhibits the dimerization and activation of EGFR. Therefore, EGCG inhibits the Ras/MAPK and PI3K/Akt signaling pathways, which are RTK-related cell signaling pathways, as well as the activation of AP-1 and NF-kappaB, thereby modulating the expression of target genes which are associated with induction of apoptosis and cell cycle arrest in cancer cells. These findings are significant because abnormalities in the expression and function of RTKs and their downstream effectors play a critical role in the development of several types of human malignancies. In this paper we review evidence indicating that EGCG exerts anticancer effects, at least in part, through inhibition of activation of the specific RTKs and conclude that targeting RTKs and related signaling pathway by tea catechins might be a promising strategy for the prevention of human cancers.

Keywords: AP-1, activator protein-1; COX-2, cyclooxygenase-2; EC, (–)-epicatechin; ECG, epicatechin-3-gallate; EGC, (–)-epigallocatechin; EGCG; EGCG, (–)-epigallocatechin-3-gallate; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; HNSCC, head and neck squamous cell carcinoma; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; IGFBP, insulin-like growth factor-binding protein; IKKα, inhibitor of κB kinase-α; IκBα, inhibitor of κB-α; LR, laminin receptor; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; PGE2prostaglandin E2; PI3K, phosphatidylinositol 3-kinase; Poly E, polyphenon E; ROS, reactive oxygen species; RTK; RTK, receptor tyrosine kinase; Stat, signal transducers and activator of transcription; TGFα, transforming growth factor-α; TRAMP, transgenic adenocarcinoma of mouse prostate; Tea catechins; UV, ultraviolet; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; cell signaling pathway.

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Figures

Figure 1.
Figure 1.
Chemical structure of EGCG.
Figure 2.
Figure 2.
Schematic representation of the erbB family and the IGF/IGF-1R system. (A) The family of erbB receptors includes four members: EGFR (erbB1), HER2 (neu/erbB2), HER3 (erbB3), and HER4 (erbB4). All members have an extracellular ligand binding region (cysteine rich domain), a single membrane-spanning region, and a cytoplasmic tyrosine-kinase-containing domain. Ligand, such as TGF-α etc, binding to erbB receptors induces the formation of receptor homo- and heterodimers and the activation of the intrinsic kinase domain, thus resulting in phosphorylation on specific tyrosine residues within the cytoplasmic tail. These phosphorylated residues serve as docking sites for a range of proteins, the recruitment of which leads to the activation of intracellular signaling pathways, including the Ras/MAPK and PI3K/Akt pathways. (B) The IGF/IGF-1R system is composed of ligands (IGF-1 and IGF-2), receptor (IGF-1R), and ligand binding proteins (IGFBPs). IGF-1 and IGF-2 are found in the circulation complexed to IGFBPs, which serve to regulate the bioavailability of these ligands in the tissues. The IGF-1R contains two α (cysteine rich domain) and two β (tyrosine kinase domain) subunits which are joined by disulfide bridges to form a heterotetrameric receptor complex. The IGF/IGF-1R interaction results in phosphorylation of tyrosine residues in the tyrosine kinase domain. After autophosphorylation, the receptor kinase phosphorylates intracellular proteins, which enable activation of the PI3K/Akt and Ras/MAPK signaling pathways. A detailed description of the downstream signaling pathway is provided in “Figure 3”.
Figure 3.
Figure 3.
A simplified scheme indicating how the activation of RTKs induces pathways of signal transduction which lead to the activation of the transcription factors AP-1 and NF-κB. RTKs, like EGFR and IGF-1R, are activated by specific ligands, thus leading to the activation of their intrinsic tyrosine kinase and autophosphorylation of tyrosine residues. These activated RTKs then phosphorylate several downstream molecules, thus activating several signaling pathways. The activation of the small G protein Ras and effector proteins, such as Raf-1 and PI3K, stimulates several intracellular processes. As a result, the activated Raf-1 stimulates the MEK1/2 and its cascade which then phosphorylate the MAPK protein ERK1/2. Once activated, MAPKs can activate a variety of transcription factors, including ELK and c-Jun. The binding of AP-1, a dimeric complex that comprises members of the Jun and Fos families of transcription factors, to the TRE DNA sequence in various gene promoters, activates the expression of target genes. PI3Ks are heterodimeric lipid kinases that are composed of a regulatory (p85) and a catalytic (p110) subunit. The activation of PI3K causes the synthesis of the lipid PIP3, which activates the downstream pathways that involve Akt. Akt and NIK both play a role in the phosphorylation and activation of the kinase IKK. Activated IKK phosphorylates IκB, which triggers ubiquitinylation (Ub) and the subsequent degradation of IκB. The loss of IκB releases Rel from an inactive complex, which then translocates from the cytoplasm to the nucleus where it can activate the transcription of target genes. Molecules that appear to be cellular targets for the action of EGCG are indicated by blue (downregulation) or orange (upregulation) arrows. These multiple effects of EGCG finally lead to the inhibition of cell proliferation and the induction of apoptosis in cancer cells
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