Journal
EUROPEAN JOURNAL OF CANCER
Volume 45, Issue 12, Pages 2219-2227Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2009.05.017
Keywords
Nrf2; 5-Fluorouracil; Chemoresistance; Colon cancer cells; Antioxidant enzymes; Glutathione transferase
Categories
Funding
- Institut National de la Sante et de la Recherche Medicale
- Association pour la Recherche sur le Cancer (ARC)
- Conseil National de la Recherche Scientifique du Liban
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Acquisition of drug resistance by cancer cells is attributed to various factors including alterations in apoptotic pathways, enhanced expression of multidrug resistance-associated proteins, altered drug metabolism or uptake and/or overexpression. of cytoprotective genes. Thus, potential induction of defence pathways by anticancer drugs might have a marked incidence on cancer cell resistance. 5-Fluorouracil (5-FU) remains the most commonly used anticancer drug for the treatment of colorectal cancer, although objective response rates are as low as 20%. The aim of our study was to investigate the effects of 5-FU on cytoprotective systems in human colon HT-29 cells. Our results demonstrate that 5-FU induced the expression of mRNAs encoding glutathione transferases and antioxidant enzymes. To further determine the mechanisms involved in 5-FU effects, we investigated whether it activates the Nrf2/antioxidant response element pathway which is implicated in the regulation of several genes involved in cytoprotection. Translocation of Nrf2 into the nucleus after 5-FU exposure was demonstrated by immunocytochemistry and western blotting. Using an ARE-driven reporter gene assay, activation of the luciferase activity by 5-FU was also evidenced. Moreover, transfection of HT-29 cells with siRNA directed against Nrf2 inhibited induction of Nrf2 target genes and increased 5-FU cytotoxicity. in conclusion, we demonstrate for the first time that 5-FU activates the Nrf2/ARE pathway which in turn induces cytoprotective genes and modulates chemosensitivity, of HT-29 colon cancer cells. Therefore, we postulate that Nrf2 might represent a potential therapeutic target in 5-FU treatment of colon cancer. (C) 2009 Elsevier Ltd. All rights reserved.
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