Abstract 1611: EGCG inhibits growth of human pancreatic tumors orthotopically implanted in BALB/c Nude mice through activation of FKHRL1/FOXO3a transcription factor.

Abstract

Abstract 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 EGCG 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. FKHRL1 nuclear translocation, and DNA binding were measured by immunohistochemistry and gelshift assay, respectively. The expression of PI3K, AKT, ERK, and FOXO3a and its target genes were measured by the Western blot analysis. EGCG-treated mice showed significant inhibition in tumor growth which was associated with reduced phosphorylation of ERK, PI3K, AKT, FKHRL1/FOXO3a and expression of FOXO target genes. EGCG induced apoptosis by up-regulating Bim and activating caspase-3. EGCG inhibited markers of cell cycle (p27/KIP1), angiogenesis (CD31, VEGF, IL-6, IL-8 and HIF1α), and metastasis (MMP2 and MMP7). 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 resulting in activation of FKHRL1/FOXO3a transcription factor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1611. doi:1538-7445.AM2012-1611