Epigallocatechin-3-gallate decreases VEGF production in head and neck and breast carcinoma cells by inhibiting EGFR-related pathways of signal transduction

• Published in: Journal of experimental therapeutics & oncology Vol. 2; no. 6; p. 350
• Main Authors: Masuda, Muneyuki, Suzui, Masumi, Lim, Jin T E, Deguchi, Atsuko, Soh, Jae-Won, Weinstein, I Bernard
• Format: Journal Article
• Language: English
• Published: United States 01.11.2002
• Subjects: Antineoplastic Agents - pharmacology; Breast Neoplasms - metabolism; Carcinoma, Squamous Cell - metabolism; Catechin - analogs & derivatives; Catechin - pharmacology; Chromones - pharmacology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endothelial Growth Factors - biosynthesis; Endothelial Growth Factors - genetics; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; Flavonoids - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Head and Neck Neoplasms - metabolism; Humans; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - genetics; Luciferases - metabolism; Lymphokines - biosynthesis; Lymphokines - genetics; MAP Kinase Kinase Kinase 1; Mitogen-Activated Protein Kinases - metabolism; Models, Biological; Morpholines - pharmacology; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Signal Transduction - drug effects; STAT3 Transcription Factor; Trans-Activators - genetics; Trans-Activators - metabolism; Transfection; Transforming Growth Factor alpha - metabolism; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator - antagonists & inhibitors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
• ISSN: 1359-4117
• DOI: 10.1046/j.1359-4117.2002.01062.x

In a recent study on head and neck squamous cell carcinoma (HNSCC) cells we found that epigallocatechin-3-gallate (EGCG), a major biologically active component of green tea, inhibited activation of the epidermal growth factor receptor (EGFR) and related signaling pathways. Since activation of EGFR signaling pathways is associated with angiogenesis, we examined the effects of EGCG on vascular endothelial growth factor (VEGF) production by YCU-H891 HNSCC and MDA-MB-231 breast carcinoma cell lines, because we found that both of these cell lines display autocrine activation of transforming growth factor-alpha (TGF-alpha)/EGFR signaling and produce high levels of VEGF. Treatment with EGCG inhibited the constitutive activation of the EGFR, Stat3, and Akt in both cell lines. These changes were associated with inhibition of VEGF promoter activity and cellular production of VEGF. Mechanistic studies indicated that inhibition of Stat3, but not mitogen-activated protein kinase kinase (MEK)1 or phosphatidylinositol 3'-kinase (PI3K), significantly decreased VEGF promoter activity. However, the inhibitory effects of a dominant negative Stat3 on VEGF expression was not as strong as that produced by EGCG. An analysis of alternative pathways indicated that EGCG strongly inhibited the constitutive activation of NF-kappa B in both cell lines, and an NF-kappa B inhibitor strongly inhibited VEGF production. These results suggest that EGCG inhibits VEGF production by inhibiting both the constitutive activation of Stat3 and NF-kappa B, but not extracellular-signal-regulated kinase (ERK) or Akt, in these cells. Therefore, EGCG may be useful in treating HNSCC and breast carcinoma because it can exert both antiproliferative and antiangiogenic activities.