Inhibition of PI3K/AKT and MEK/ERK pathways act synergistically to enhance antiangiogenic effects of EGCG through activation of FOXO transcription factor

Sharmila Shankar,Qinghe Chen,Rakesh K Srivastava

doi:10.1186/1750-2187-3-7

Abstract

BackgroundWe have recently shown that epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, inhibits angiogenesis. However, the molecular mechanisms by which EGCG inhibits angiogenesis have never been investigated. In this study, we examined the interaction of PI3K/AKT and MEK/ERK pathways on the regulation of FOXO transcription factors, which ultimately control the antiangiogenic effects of EGCG.ResultsInhibition of PI3K/AKT and MEK/ERK pathways interact synergistically to inhibit migration and capillary tube formation of HUVEC cells and further enhanced the antiangiogenic effects of EGCG. Inhibition of AKT and MEK kinases synergistically induced FOXO transcriptional activity, which was further enhanced in the presence of EGCG. Phosphorylation deficient mutants of FOXO induced FOXO transcriptional activity, inhibited HUVEC cell migration and capillary tube formation. Inhibition of FOXO phosphorylation also enhanced antiangiogenic effects of EGCG through transcriptional activation of FOXO.ConclusionInhibition of PI3K/AKT and MEK/ERK pathways act synergistically to regulate antiangiogenic effects of EGCG through activation of FOXO transcription factors. The activation of FOXO transcription factors through inhibition of these two pathways may have physiological significance in management of diabetic retinopathy, rheumatoid arthritis, psoriasis, cardiovascular diseases, and cancer.

Highlights

We have recently shown that epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, inhibits angiogenesis
Involvement of PI3 kinase (PI3K)/AKT and MEK/extracellular signal-regulated protein kinase (ERK) pathways on EGCG-induced apoptosis We first measured the involvement of PI3K/AKT and MEK/ERK pathways on EGCG-induced apoptosis in Human umbilical vein endothelial cells (HUVECs) cells
AKT inhibitor and MEK inhibitor, alone or in combination, enhanced the proapoptotic effects of EGCG in HUVEC cells. These data suggest that inhibition of PI3K/AKT and MEK/ERK pathways act synergistically to enhance the antiapoptotic effects of EGCG

Summary

Introduction

We have recently shown that epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, inhibits angiogenesis. Angiogenesis is a complex event which requires endothelial cell sprouting, lumen formation, tubulogenesis and is regulated by the coordinated action of different transcription factors [1,2]. Their interaction leads to endothelial cell differentiation and acquisition of arterial, venous and lymphatic properties. The FOXO subgroup regulates the correct organization of the vascular system, controlling excessive endothelial growth and inducing apoptosis in both embryos and adult mice. Many members of this family are expressed very early in the developing vasculature. FOXO transcription factors play a crucial role in the regulation of tissue homeostasis in organs such as the pancreas and the ovaries and com-

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