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

Abstract

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.

Oral Cancer Prevention Advances with a Translational Trial of Green Tea

“…GTE treatment was well tolerated, although higher doses increased insomnia and nervousness (albeit without grade 4 toxicities). This study also provided some very important biomarker data, including data on VEGF that are consistent with previously reported effects of GTE (18,31). Baseline stromal VEGF levels correlated with clinical (P = 0.04) but not histologic response.…”

Soy intake and breast cancer: elucidation of an unanswered question

“…Flavonoids, of which soy-based isoflavones are the most intensely studied, lower endogenous hormone levels in pre- (Dai et al, 2002;Ren et al, 2003) and post-menopausal women (Murkies et al, 1995), and inhibit transcriptional factors involved in cancer metastasis (Valachovicova et al, 2004;Slivova et al, 2005), including vascular endothelial growth factor, which is strongly associated with tumour angiogenesis (Masuda et al, 2002). These findings provide support for a biologically plausible association between dietary intake of flavonoids, particularly isoflavones, on breast cancer risk and prognosis.…”

Green tea catechin, epigallocatechin‐3‐gallate, inhibits vascular endothelial growth factor angiogenic signaling by disrupting the formation of a receptor complex

“…22,23 EGCG has also been shown to inhibit endothelial cell proliferation, VEGF receptor binding, VEGFR-2 phosphorylation, VEGFR-2 expression and matrix metalloproteinase activity in endothelial cells, all processes integral to angiogenesis. [23][24][25][26][27][28][29] In a respiratory epithelial cell line, Chen et al 30 reported that EGCG can inhibit IjB kinase (IKK) activation and IL-8 gene expression. However, most of these reports on EGCG have been achieved using very high and physiologically unrealistic doses of the catechin.…”