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Targeting Receptor Tyrosine Kinases for Chemoprevention by Green Tea Catechin, EGCG

By Masahito Shimizu, Yohei Shirakami and Hisataka Moriwaki

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-κB, 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

Topics: Review
Publisher: Molecular Diversity Preservation International (MDPI)
OAI identifier: oai:pubmedcentral.nih.gov:2658783
Provided by: PubMed Central
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    Citations

    1. (2005). (-)-Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells. Clin. Cancer Res.
    2. (2005). A lipid raft-associated 67kDa laminin receptor mediates suppressive effect of epigallocatechin-3-O-gallate on FcepsilonRI expression.
    3. (2004). A receptor for green tea polyphenol EGCG.
    4. (2002). Addiction to oncogenes--the Achilles heal of cancer. Science
    5. (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell
    6. (1999). Angiogenesis inhibited by drinking tea.
    7. (1999). Antioxidant chemistry of green tea catechins. Identification of products of the reaction of (-)-epigallocatechin gallate with peroxyl radicals.
    8. (2003). AP-1: a double-edged sword in tumorigenesis.
    9. (2003). Cancer chemoprevention with dietary phytochemicals.
    10. (2000). Cell signaling by receptor tyrosine kinases. Cell
    11. (2006). Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res.
    12. (1998). Cholesterol depletion of caveolae causes hyperactivation of extracellular signal-related kinase (ERK).
    13. (2002). Cholesterol levels modulate EGF receptor-mediated signaling by altering receptor function and trafficking. Biochemistry
    14. (2004). Common and distinct elements in cellular signaling via EGF and FGF receptors. Science
    15. (2002). Cyclooxygenase isozymes and their gene structures and expression. Prostaglandins Other Lipid Mediat.
    16. (2003). Detoxifying cancer causing agents to prevent cancer. Integr. Cancer Ther.
    17. (2001). Effects of epigallocatechin-3-gallate on growth, epidermal growth factor receptor signaling pathways, gene expression, and chemosensitivity in human head and neck squamous cell carcinoma cell lines. Clin. Cancer Res.
    18. (2008). EGCG and polyphenon E attenuate inflammation-related mouse colon carcinogenesis induced by AOM
    19. EGCG inhibits activation of HER3 and expression of cyclooxygenase-2 in human colon cancer cells.
    20. (2008). EGCG inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells. Cancer Lett.
    21. (2005). EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells.
    22. Epigallocatechin-3-gallate decreases VEGF production in head and neck and breast carcinoma cells by inhibiting EGFR-related pathways of signal transduction.
    23. (2003). Epigallocatechin-3-gallate inhibits activation of HER-2/neu and downstream signaling pathways in human head and neck and breast carcinoma cells. Clin. Cancer Res.
    24. (2004). Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinases.
    25. (2005). ERBB receptors and cancer: the complexity of targeted inhibitors.
    26. (1997). ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling.
    27. (2004). Gefitinib--a novel targeted approach to treating cancer.
    28. (2004). Genistein alters growth factor signaling in transgenic prostate model (TRAMP).
    29. (2006). Green tea catechin, epigallocatechin-3-gallate, inhibits vascular endothelial growth factor angiogenic signaling by disrupting the formation of a receptor complex.
    30. (2000). Green tea compounds inhibit tyrosine phosphorylation of PDGF beta-receptor and transformation of A172 human glioblastoma.
    31. (2002). Green tea polyphenol epigallocatechin-3 gallate inhibits Her-2/neu signaling, proliferation, and transformed phenotype of breast cancer cells. Cancer Res.
    32. (2000). Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells.
    33. (2001). Her-2/neu overexpression induces NF-kappaB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IkappaB-alpha that can be inhibited by the tumor suppressor
    34. (2006). Inflammation and cancer: How hot is the link?
    35. (2000). Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced NF-kappaB activation by tea polyphenols, (-)-epigallocatechin gallate and theaflavins. Carcinogenesis
    36. (2002). Inhibition of carcinogenesis by tea.
    37. (1995). Inhibition of ligand-induced activation of epidermal growth factor receptor tyrosine phosphorylation by curcumin. Carcinogenesis
    38. Inhibition of the vascular-endothelial growth factor-induced intracellular signaling and mitogenesis of human endothelial cells by epigallocatechin-3 gallate.
    39. (1997). Inhibition of tumor promoter-induced activator protein 1 activation and cell transformation by tea polyphenols, (-)-epigallocatechin gallate, and theaflavins. Cancer Res.
    40. Inhibition of ultraviolet B-mediated activation of nuclear factor kappaB in normal human epidermal keratinocytes by green tea Constituent (-)-epigallocatechin-3-gallate.
    41. (2004). Insulin-like growth factors and neoplasia.
    42. (2001). Mammalian MAP kinase signalling cascades.
    43. (1999). Mechanism-based cancer prevention approaches: targets, examples, and the use of transgenic mice.
    44. (2001). Mechanisms of inhibition of the Ras-MAP kinase signaling pathway in 30.7b Ras 12 cells by tea polyphenols (-)-epigallocatechin-3-gallate and theaflavin-3,3'-digallate.
    45. (2005). Membrane rafts segregate pro- from anti-apoptotic insulin-like growth factor-I receptor signaling in colon carcinoma cells stimulated by members of the tumor necrosis factor superfamily.
    46. (2002). Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science
    47. (2005). Modulation of signal transduction by tea catechins and related phytochemicals.
    48. (2001). Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation.
    49. (1999). NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1.
    50. (2002). NF-kappaB in cancer: from innocent bystander to major culprit.
    51. (1999). NF-kappaB is a target of AKT
    52. (2004). Nutrition and cancer: a review of the evidence for an anti-cancer diet.
    53. (1997). Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation.
    54. (2004). Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer. Cancer Res.
    55. (2003). Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin. Cancer Res.
    56. (2001). Prostaglandin E2 increases growth and motility of colorectal carcinoma cells.
    57. (2003). Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions.
    58. (2006). Role of gangliosides in the association of ErbB2 with lipid rafts in mammary epithelial HC11 cells.
    59. (1997). Screening of anticarcinogenic ingredients in tea polyphenols. Cancer Lett.
    60. (2002). Sequestration of epidermal growth factor receptors in non-caveolar lipid rafts inhibits ligand binding.
    61. (2001). Specific protection against breast cancers by cyclin D1 ablation. Nature
    62. (1997). Suppression of extracellular signals and cell proliferation through EGF receptor binding by (-)-epigallocatechin gallate in human A431 epidermoid carcinoma cells.
    63. (2006). Targeting multiple signaling pathways by green tea polyphenol (-)-epigallocatechin-3-gallate. Cancer Res.
    64. (2004). Targeting the mitogen-activated protein kinase cascade to treat cancer.
    65. (2004). Tea polyphenol epigallocatechin-3-gallate associates with plasma membrane lipid rafts: lipid rafts mediate anti-allergic action of the catechin. Biofactors
    66. (2000). Tea polyphenols: prevention of cancer and optimizing health.
    67. The biology of VEGF and its receptors.
    68. (2000). The ErbB signaling network: receptor heterodimerization in development and
    69. (2007). The inhibitory effect of (-)-epigallocatechin gallate on activation of the epidermal growth factor receptor is associated with altered lipid order in HT29 colon cancer cells. Cancer Res.
    70. (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer.
    71. (1997). The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal.
    72. (1995). Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions.
    73. (2002). Up-regulation of cyclooxygenase-2 expression and prostaglandin synthesis in endometrial stromal cells by malignant endometrial epithelial cells. A paracrine effect mediated by prostaglandin E2 and nuclear
    74. (2004). Vascular endothelial growth factor as a target for anticancer therapy. Oncologist

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