Molecular and Cellular Biochemistry

, Volume 372, Issue 1–2, pp 83–94

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

  • Sharmila Shankar
  • Luke Marsh
  • Rakesh K. Srivastava
Article

DOI: 10.1007/s11010-012-1448-y

Cite this article as:
Shankar, S., Marsh, L. & Srivastava, R.K. Mol Cell Biochem (2013) 372: 83. doi:10.1007/s11010-012-1448-y

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.

Keywords

Pancreatic cancer EGCG Cancer prevention FOXO 

Abbreviations

bHLH

Basic helix-loop-helix

Cbp

CREB-binding protein

EC

Endothelial cells

ECM

Extracellular matrix

EGCG

(−)-Epigallocatechin-3-gallate

ERK1/2

Extracellular signal-regulated kinase

EMT

Epithelial-mesenchymal transition

FOXO

Forkhead transcription factors of the O class

HREs

Hypoxia response elements

HIF

Hypoxia-inducible factor

MMP

Matrix metalloproteinases

NRP2

Neuropilin-2

PI3K

Phosphoinositide 3-kinase

PDA

Pancreatic ductal adenocarcinoma

Pcaf

p300/CBP-associated factors

SEMA 3F

Semaphorin 3F

VEGF

Vascular endothelial growth factor

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Sharmila Shankar
    • 1
  • Luke Marsh
    • 2
  • Rakesh K. Srivastava
    • 3
  1. 1.Department of Pathology and Laboratory MedicineThe University of Kansas Cancer Center, The University of Kansas Medical CenterKansas CityUSA
  2. 2.Department of BiochemistryUniversity of Texas Health Science Center at TylerTylerUSA
  3. 3.Department of Pharmacology, Toxicology and Therapeutics, and MedicineThe University of Kansas Cancer Center, The University of Kansas Medical CenterKansas CityUSA

Personalised recommendations