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Title: Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells

Abstract

Highlights: Black-Right-Pointing-Pointer We investigate mechanisms responsible for butyrate resistance in colon cancer cells. Black-Right-Pointing-Pointer Tcf3 modulates butyrate's effects on Wnt activity and cell growth in resistant cells. Black-Right-Pointing-Pointer Tcf3 modulation of butyrate's effects differ by cell context. Black-Right-Pointing-Pointer Cell cycle factors are overexpressed in the resistant cells. Black-Right-Pointing-Pointer Reversal of altered gene expression can enhance the anti-cancer effects of butyrate. -- Abstract: Butyrate, a fermentation product of dietary fiber, inhibits clonal growth in colorectal cancer (CRC) cells dependent upon the fold induction of Wnt activity. We have developed a CRC cell line (HCT-R) that, unlike its parental cell line, HCT-116, does not respond to butyrate exposure with hyperactivation of Wnt signaling and suppressed clonal growth. PCR array analyses revealed Wnt pathway-related genes, the expression of which differs between butyrate-sensitive HCT-116 CRC cells and their butyrate-resistant HCT-R cell counterparts. We identified overexpression of Tcf3 as being partially responsible for the butyrate-resistant phenotype, as this DNA-binding protein suppresses the hyperinduction of Wnt activity by butyrate. Consequently, Tcf3 knockdown in HCT-R cells restores their sensitivity to the effects of butyrate on Wnt activity and clonal cell growth. Interestingly, the effects of overexpressed Tcf3 differ between HCT-116 and HCT-R cells; thus, in HCT-116 cellsmore » Tcf3 suppresses proliferation without rendering the cells resistant to butyrate. In HCT-R cells, however, the overexpression of Tcf3 inhibits Wnt activity, and the cells are still able to proliferate due to the higher expression levels of cell cycle factors, particularly those driving the G{sub 1} to S transition. Knowledge of the molecular mechanisms determining the variable sensitivity of CRC cells to butyrate may assist in developing approaches that prevent or reverse butyrate resistance.« less

Authors:
 [1];  [1];  [1]
  1. Department of Basic Sciences, The Commonwealth Medical College, 525 Pine Street, Scranton, PA 18509 (United States)
Publication Date:
OSTI Identifier:
22210324
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 428; Journal Issue: 1; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL GROWTH; CELL CYCLE; CELL PROLIFERATION; DNA; FERMENTATION; GENES; LARGE INTESTINE; NEOPLASMS; PHENOTYPE; POLYMERASE CHAIN REACTION; SENSITIVITY

Citation Formats

Chiaro, Christopher, E-mail: cchiaro@tcmedc.org, Lazarova, Darina L., E-mail: dlazarova@tcmedc.org, and Bordonaro, Michael, E-mail: mbordonaro@tcmedc.org. Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells. United States: N. p., 2012. Web. doi:10.1016/J.BBRC.2012.10.018.
Chiaro, Christopher, E-mail: cchiaro@tcmedc.org, Lazarova, Darina L., E-mail: dlazarova@tcmedc.org, & Bordonaro, Michael, E-mail: mbordonaro@tcmedc.org. Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells. United States. doi:10.1016/J.BBRC.2012.10.018.
Chiaro, Christopher, E-mail: cchiaro@tcmedc.org, Lazarova, Darina L., E-mail: dlazarova@tcmedc.org, and Bordonaro, Michael, E-mail: mbordonaro@tcmedc.org. Fri . "Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells". United States. doi:10.1016/J.BBRC.2012.10.018.
@article{osti_22210324,
title = {Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells},
author = {Chiaro, Christopher, E-mail: cchiaro@tcmedc.org and Lazarova, Darina L., E-mail: dlazarova@tcmedc.org and Bordonaro, Michael, E-mail: mbordonaro@tcmedc.org},
abstractNote = {Highlights: Black-Right-Pointing-Pointer We investigate mechanisms responsible for butyrate resistance in colon cancer cells. Black-Right-Pointing-Pointer Tcf3 modulates butyrate's effects on Wnt activity and cell growth in resistant cells. Black-Right-Pointing-Pointer Tcf3 modulation of butyrate's effects differ by cell context. Black-Right-Pointing-Pointer Cell cycle factors are overexpressed in the resistant cells. Black-Right-Pointing-Pointer Reversal of altered gene expression can enhance the anti-cancer effects of butyrate. -- Abstract: Butyrate, a fermentation product of dietary fiber, inhibits clonal growth in colorectal cancer (CRC) cells dependent upon the fold induction of Wnt activity. We have developed a CRC cell line (HCT-R) that, unlike its parental cell line, HCT-116, does not respond to butyrate exposure with hyperactivation of Wnt signaling and suppressed clonal growth. PCR array analyses revealed Wnt pathway-related genes, the expression of which differs between butyrate-sensitive HCT-116 CRC cells and their butyrate-resistant HCT-R cell counterparts. We identified overexpression of Tcf3 as being partially responsible for the butyrate-resistant phenotype, as this DNA-binding protein suppresses the hyperinduction of Wnt activity by butyrate. Consequently, Tcf3 knockdown in HCT-R cells restores their sensitivity to the effects of butyrate on Wnt activity and clonal cell growth. Interestingly, the effects of overexpressed Tcf3 differ between HCT-116 and HCT-R cells; thus, in HCT-116 cells Tcf3 suppresses proliferation without rendering the cells resistant to butyrate. In HCT-R cells, however, the overexpression of Tcf3 inhibits Wnt activity, and the cells are still able to proliferate due to the higher expression levels of cell cycle factors, particularly those driving the G{sub 1} to S transition. Knowledge of the molecular mechanisms determining the variable sensitivity of CRC cells to butyrate may assist in developing approaches that prevent or reverse butyrate resistance.},
doi = {10.1016/J.BBRC.2012.10.018},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 1,
volume = 428,
place = {United States},
year = {2012},
month = {11}
}