EGCG inhibits growth of human pancreatic tumors orthotopically implanted in Balb C nude mice through modulation of FKHRL1/FOXO3a and neuropilin.

Abstract

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.

• Authors: Sharmila Shankar, Luke Marsh, Rakesh K Srivastava
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 372 Issue 1-2 Pg. 83-94 (Jan 2013) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 22971992 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Biomarkers, Tumor
• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• Neuropilins
• Proliferating Cell Nuclear Antigen
• Catechin
• epigallocatechin gallate

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Pancreatic Ductal (blood supply, drug therapy, metabolism, pathology)
• Catechin (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Gene Expression (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MAP Kinase Signaling System (drug effects)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neovascularization, Pathologic (prevention & control)
• Neuropilins (metabolism)
• Pancreas (pathology)
• Pancreatic Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Proliferating Cell Nuclear Antigen (metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays