Abstract
Vasculogenic mimicry (VM) is the alternative process of forming vessel-like networks by aggressive tumor cells, and it has an important role in tumor survival, growth, and metastasis. Epigallocatechin-3-gallate (EGCG) is well known to have diverse bioactivities including anti-cancer effects. However, the efficacy of EGCG on VM is elusive. In this study, we explored whether and how EGCG affects VM in human prostate cancer (PCa) PC-3 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Invasive and VM formation abilities were assessed by an invasion assay and a three-dimensional (3D) culture VM tube formation assay, respectively. Western blots were carried out. An immunofluorescence assay was performed to detect nuclear twist expression. EGCG effectively inhibited the invasive ability, as well as tubular channel formation, without affecting cell viability. EGCG significantly downregulated the expression of vascular endothelial cadherin (VE-cadherin) and its transcription factor, twist, N-cadherin, vimentin, phosphor-AKT, and AKT, but not phospho-erythropoietin-producing hepatocellular receptor A2 (EphA2) and EphA2. In addition, EGCG diminished the nuclear localization of twist. Treatment with SC79, an AKT activator, effectively rescued EGCG-inhibited VM formation. These results demonstrated for the first time that EGCG causes marked suppression of VM through inhibiting the twist/VE-cadherin/AKT pathway in human PCa PC-3 cells.
Highlights
Blood supply is required to promote tumor growth, survival, and metastasis [1]
VE-cadherin expression was strikingly downregulated by ECGC treatment in a dose-dependent manner (Figure 4A). These results revealed that the downregulation of VE-cadherin but not erythropoietin-producing hepatocellular receptor A2 (EphA2) is associated with EGCG-inhibited Vasculogenic mimicry (VM) formation in PC-3 cells
N-cadherin and vimentin expression was downregulated by EGCG in a dose-dependent manner (Figure 4D). These results indicated that EGCG inhibits twist level in the nucleus, thereby downregulating VE-cadherin expression in PC-3 cells
Summary
Blood supply is required to promote tumor growth, survival, and metastasis [1]. Because angiogenesis plays important roles in tumor growth, survival, and metastasis, anti-angiogenic therapies were considered as promising and key strategies for the treatment of cancer for almost 30 years [2,4]. Anti-angiogenic drugs were not effective in all cancers, and resistance to these therapies occurred during a period of treatment [5]. Animal studies reported that anti-angiogenic therapy delays tumor growth, followed by tumor regrowth [6]. These researches demonstrated that tumor cells can evade the therapeutic effects of anti-angiogenic drugs and suggested that these phenomena may be due to adequate blood supply via alternative pathways
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