Multidrug-resistant protein-3 gene regulation by the transcription factor Nrf2 in human bronchial epithelial and non-small-cell lung carcinoma
| Autor: | Philip C. Mack, Henry Jay Forman, Christopher M. Mahaffey, Alessandra Rinna, W. S. Holland, Hongqiao Zhang |
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| Rok vydání: | 2009 |
| Předmět: |
Lung Neoplasms
NF-E2-Related Factor 2 Molecular Sequence Data Bronchi Biology Biochemistry Epithelium Article 4-Hydroxynonenal chemistry.chemical_compound Physiology (medical) Carcinoma Non-Small-Cell Lung Tumor Cells Cultured Gene silencing Humans Gene Silencing RNA Messenger RNA Small Interfering Promoter Regions Genetic Transcription factor Regulation of gene expression Aldehydes Base Sequence respiratory system KEAP1 Molecular biology Up-Regulation Gene Expression Regulation Neoplastic chemistry Cytoplasm Cell culture Cancer research Cisplatin Multidrug Resistance-Associated Proteins |
| Zdroj: | Free radical biologymedicine. 46(12) |
| ISSN: | 1873-4596 |
| Popis: | Multidrug Resistant Proteins (MRP) are members of the ATP-binding cassette superfamily that facilitate detoxification by transporting toxic compounds, including chemotherapeutic drugs, out of cells. Chemotherapy, radiation, and other xenobiotic stresses have been shown to increase levels of select MRPs, although, the underlying mechanism remains largely unknown. Additionally, MRP3 is suspected of playing a role in the drug resistance of non-small cell lung carcinoma (NSCLC). Analysis of the MRP3 promoter revealed the presence of multiple putative electrophile responsive elements (EpRE), sequences that suggested possible regulation of this gene by Nrf2, the key transcription factor that binds to EpRE. The goal of this investigation was to determine whether MRP3 induction was dependent upon the transcription factor Nrf2. Keap1, a key regulator of Nrf2, sequesters Nrf2 in the cytoplasm, preventing entry into the nucleus. The electrophilic lipid peroxidation product, 4-hydroxy-2-nonenal (HNE) has been shown to modify Keap1 allowing Nrf2 to enter the nucleus. We found that HNE up-regulated MRP3 mRNA and protein levels in cell lines with wild type Keap1 (human bronchial epithelial cell line HBE1 and the NSCLC cell line H358), but not in the Keap1 mutant NSCLC cell lines (A549 and H460). Cell lines with mutant Keap1 had constitutively higher MRP3 that was not increased by HNE treatment. In HBE1 cells, silencing of Nrf2 with siRNA inhibited induction of MRP3 and by HNE. Finally, we found that silencing Nrf2 also increased the toxicity of cisplatin in H358 cells. The combined results therefore support the hypothesis that MRP3 induction by HNE involves Nrf2 activation. |
| Databáze: | OpenAIRE |
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