Involvement of Nrf2 activation in resistance to 5-fluorouracil in human colon cancer HT-29 cells
| Autor: | Pascal Loyer, Anne Corlu, André Guillouzo, Claudine Rauch, Hanane Akhdar, Fabrice Morel |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Cancer Research Antimetabolites Antineoplastic Colorectal cancer NF-E2-Related Factor 2 Apoptosis Biology medicine Humans Reporter gene Cancer Transfection Suicide gene medicine.disease Cytoprotection Gene Expression Regulation Neoplastic Oncology Biochemistry Drug Resistance Neoplasm Cancer cell Colonic Neoplasms Cancer research Female Fluorouracil HT29 Cells Drug metabolism |
| Zdroj: | European journal of cancer (Oxford, England : 1990). 45(12) |
| ISSN: | 1879-0852 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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