Green tea catechins inhibit angiogenesis through suppression of STAT3 activation

Abstract

Previous studies indicate that green tea extract may inhibit breast cancer progression by blocking angiogenesis, although the molecular mechanisms are not well defined. We demonstrate that administration of Polyphenon E (Poly E), a standardized green tea extract, inhibited MDA-MB231 breast cancer and human dermal microvascular endothelial (HMVEC) cell migration and the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP9). In addition, Poly E inhibited VEGF-induced neovascularization in vivo. We also demonstrate that Poly E blocked signal transducers and activators of transcription (STAT) signaling by suppressing interferon-gamma (IFN-γ)-induced gene transcription via IFN-γ-activating sequence (GAS) elements and downstream STAT3 activation by inhibiting STAT1 and STAT3 dimerization in MDA-MB231 cells. Transient expression of constitutively active STAT3 significantly reduced the inhibitory effect of Poly E on cell migration and VEGF and MMP9 expression. Taken together, these observations indicate that green tea extract inhibits angiogenesis partly through the disruption of STAT3-mediated transcription of genes, including VEGF.

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.…”

“…Green tea polyphenols inhibit the angiogenesis of breast cancer cells by inhibiting the expression of VEGF and MMP-9 through suppressing signal transducers and activators of transcription-3 activation (17,18). EGCG also inhibited cell viability, capillary tube formation, and migration of human umbilical vein endothelial cells and inhibited angiogenic and metastasis markers (VEGF, CD31, MMP-2, MMP-7, MMP-9, and MMP-12) in a xenograft model of pancreatic cancer (19).…”

CUEDC2 (CUE Domain-containing 2) and SOCS3 (Suppressors of Cytokine Signaling 3) Cooperate to Negatively Regulate Janus Kinase 1/Signal Transducers and Activators of Transcription 3 Signaling

“…1B). To exclude the nonspecific effect that may be caused by the ␣ 1 -antichymotrypsin reporter gene, the same experiments were performed by using other STAT3-responsive luciferase reporter constructs of GAS (IFN-␥-activating sequence) reporter and m67 reporter (a synthetic STAT3-responsive promoter) (31,32), and the results showed that CUEDC2 also inhibits the expression of these two reporters in a dose-dependent manner ( . 24 h after transfection cells were stimulated by IFN-␣ (50 ng/ml) for the indicate periods, and total cell lysates were immunoblotted using anti-p-STAT3 (Tyr-705), anti-FLAG and anti-HA antibodies.…”

JAK2/STAT3 signaling pathway activation mediates tumor angiogenesis by upregulation of VEGF and bFGF in non-small-cell lung cancer

“…Accumulating evidence supports a pivotal role of constitutively activated STAT3 in tumor angiogenesis [11]. In a wide range of cancers, including breast cancer, gastric cancer, head and neck cancer, pancreatic cancer, and melanoma, immunohistochemical studies have indicated that angiogenesis is directly correlated with constitutively elevated STAT3 activity [12][13][14][15]. Not surprisingly, angiogenesis is a complex multistage process and is regulated by the balance between angiogenesis and angiogenic factors.…”