Involvement of Nrf2 activation in resistance to 5-fluorouracil in human colon cancer HT-29 cells

• Published in: European journal of cancer (1990) Vol. 45; no. 12; pp. 2219 - 2227
• Main Authors: Akhdar, Hanane, Loyer, Pascal, Rauch, Claudine, Corlu, Anne, Guillouzo, André, Morel, Fabrice
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01-08-2009; Elsevier
• Subjects: 5-Fluorouracil; Antimetabolites, Antineoplastic - pharmacology; Antioxidant enzymes; Apoptosis - genetics; Biological and medical sciences; Chemoresistance; Colon cancer cells; Colonic Neoplasms - drug therapy; Drug Resistance, Neoplasm - genetics; Female; Fluorouracil - pharmacology; Gene Expression Regulation, Neoplastic; Glutathione transferase; Hematology, Oncology and Palliative Medicine; HT29 Cells; Humans; Male; Medical sciences; NF-E2-Related Factor 2 - drug effects; NF-E2-Related Factor 2 - metabolism; Nrf2; Pharmacology. Drug treatments; Tumors; Colon cancer cells; 5-Fluorouracil; Nrf2; Glutathione transferase; Antioxidant enzymes; Chemoresistance; Antineoplastic agent; Colon cancer; Cancerology; Intestinal disease; Tumor cell; Fluorouracil; Human; Treatment resistance; Enzyme; Fluoropyrimidine derivatives; Transferases; Enzyme inhibitor; Malignant tumor; Thymidylate synthase; Antioxidant; Colonic disease; Antimetabolic; Methyltransferases; Pyrimidine derivatives; Digestive diseases; Cancer
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2009.05.017

Abstract 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.