Department of Pathology and Laboratory Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Mol Cell Biochem. 2013 Jan;372(1-2):83-94. doi: 10.1007/s11010-012-1448-y. Epub 2012 Sep 13.
Human pancreatic cancer is currently one of the fourth leading causes of cancer-related mortality with a 5-year survival rate of less than 5 %. Since pancreatic carcinoma is largely refractory to conventional therapies, there is a strong medical need for the development of novel and innovative cancer preventive strategies. The forkhead transcription factors of the O class (FOXO) play a major role in cell proliferation, angiogenesis, metastasis, and tumorigenesis. The objectives of this study were to examine whether FKHRL1/FOXO3a modulates antitumor activity of (-)-epigallocatechin-3-gallate (EGCG), an active ingredient in green tea, in pancreatic cancer model in vivo. PANC-1 cells were orthotopically implanted into Balb c nude mice and gavaged with EGCG after tumor formation. Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining, respectively. The expression of PI3K, AKT, ERK, and FOXO3a/FKHRL1 and its target genes were measured by the western blot analysis and/or q-RT-PCR. FOXO-DNA binding was measured by gel shift assay. EGCG-treated mice showed significant inhibition in tumor growth which was associated with reduced phosphorylation of ERK, PI3K, AKT, and FKHRL1/FOXO3a, and modulation of FOXO target genes. EGCG induced apoptosis by upregulating Bim and activating caspase-3. EGCG modulated markers of cell cycle (p27/KIP1), angiogenesis (CD31, VEGF, IL-6, IL-8, SEMA3F, and HIF1α), and metastasis (MMP2 and MMP7). The inhibition of VEGF by EGCG was associated with suppression of neuropilin. EGCG inhibited epithelial-mesenchymal transition by upregulating the expression of E-cadherin and inhibiting the expression of N-cadherin and Zeb1. These data suggest that EGCG inhibits pancreatic cancer orthotopic tumor growth, angiogenesis, and metastasis which are associated with inhibition of PI3K/AKT and ERK pathways and activation of FKHRL1/FOXO3a. As a conclusion, EGCG can be used for the prevention and/or treatment of pancreatic cancer.
人类胰腺癌目前是癌症相关死亡率的第四大主要原因，其 5 年生存率低于 5%。由于胰腺癌对常规治疗大多具有抗性，因此强烈需要开发新的创新性癌症预防策略。O 类叉头转录因子（FOXO）在细胞增殖、血管生成、转移和肿瘤发生中起主要作用。本研究的目的是研究 FKHR L1/FOXO3a 是否调节绿茶中有效成分（-）-表没食子儿茶素-3-没食子酸酯（EGCG）在体内胰腺癌模型中的抗肿瘤活性。在肿瘤形成后，将 PANC-1 细胞原位植入 Balb c 裸鼠体内，并给予 EGCG 灌胃。通过 Ki67 和 TUNEL 染色分别测量细胞增殖和细胞凋亡。通过 Western blot 分析和/或 q-RT-PCR 测量 PI3K、AKT、ERK 和 FOXO3a/FKHRL1 及其靶基因的表达。通过凝胶迁移分析测量 FOXO-DNA 结合。EGCG 处理的小鼠显示出肿瘤生长的显著抑制，这与 ERK、PI3K、AKT 和 FKHRL1/FOXO3a 的磷酸化减少以及 FOXO 靶基因的调节有关。EGCG 通过上调 Bim 和激活 caspase-3 诱导细胞凋亡。EGCG 调节细胞周期标志物（p27/KIP1）、血管生成标志物（CD31、VEGF、IL-6、IL-8、SEMA3F 和 HIF1α）和转移标志物（MMP2 和 MMP7）。EGCG 通过抑制神经纤毛蛋白来抑制 VEGF。EGCG 通过上调 E-钙粘蛋白的表达和抑制 N-钙粘蛋白和 Zeb1 的表达来抑制上皮-间充质转化。这些数据表明，EGCG 抑制胰腺原位肿瘤生长、血管生成和转移，这与抑制 PI3K/AKT 和 ERK 通路和激活 FKHR L1/FOXO3a 有关。总之，EGCG 可用于预防和/或治疗胰腺癌。
