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Int. J. Mol. Sci. 2015, 16(5), 10411-10425; doi:10.3390/ijms160510411

TCF4 Is a Molecular Target of Resveratrol in the Prevention of Colorectal Cancer

Department of Nutrition and Food Science, College of Agriculture and Natural Resources, University of Maryland, College Park, MD 20742, USA
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Author to whom correspondence should be addressed.
Academic Editor: Anthony Lemarié
Received: 11 December 2014 / Revised: 30 April 2015 / Accepted: 4 May 2015 / Published: 7 May 2015
(This article belongs to the Collection Programmed Cell Death and Apoptosis)
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Abstract

The Wnt/β-catenin pathway plays an essential role in the tumorigenesis of colorectal cancer. T-cell factor-4 (TCF4) is a member of the TCF/LEF (lymphoid enhancer factor) family of transcription factors, and dysregulation of β-catenin is decisive for the initiation and progression of colorectal cancer. However, the role of TCF4 in the transcriptional regulation of its target gene remained poorly understood. Resveratrol is a dietary phytoalexin and present in many plants, including grape skin, nuts and fruits. Although resveratrol has been widely implicated in anti-tumorigenic and pro-apoptotic properties in several cancer models, the underlying cellular mechanisms are only partially understood. The current study was performed to elucidate the molecular mechanism of the anti-cancer activity of resveratrol in human colorectal cancer cells. The treatment of resveratrol and other phytochemicals decreased the expression of TCF4. Resveratrol decreases cellular accumulation of exogenously-introduced TCF4 protein, but did not change the TCF4 transcription. The inhibition of proteasomal degradation using MG132 (carbobenzoxy-Leu-Leu-leucinal) and lactacystin ameliorates resveratrol-stimulated down-regulation of TCF4. The half-life of TCF4 was decreased in the cells exposed to resveratrol. Resveratrol increased phosphorylation of TCF4 at serine/threonine residues through ERK (extracellular signal-regulated kinases) and p38-dependent pathways. The TCF4 knockdown decreased TCF/β-catenin-mediated transcriptional activity and sensitized resveratrol-induced apoptosis. The current study provides a new mechanistic link between resveratrol and TCF4 down-regulation and significant benefits for further preclinical and clinical practice. View Full-Text
Keywords: resveratrol; phytochemicals; TCF4; colon cancer resveratrol; phytochemicals; TCF4; colon cancer
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Jeong, J.B.; Lee, J.; Lee, S.-H. TCF4 Is a Molecular Target of Resveratrol in the Prevention of Colorectal Cancer. Int. J. Mol. Sci. 2015, 16, 10411-10425.

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