論文 - 詳細
| RRC ID | 6597 |
|---|---|
| 著者 | Homma S, Ishii Y, Morishima Y, Yamadori T, Matsuno Y, Haraguchi N, Kikuchi N, Satoh H, Sakamoto T, Hizawa N, Itoh K, Yamamoto M. |
| タイトル | Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:NF-E2-related factor 2 (Nrf2), a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells. In this study, therefore, the role of Nrf2 in cancer cell proliferation and resistance to anticancer drugs was investigated. EXPERIMENTAL DESIGN:We used three human lung cancer cell lines with different degrees of Nrf2 activation: Nrf2 was highly activated in A549 cells, slightly activated in NCI-H292 cells, and not activated in LC-AI cells under unstimulated conditions. RESULT:A549 cells showed higher resistance to cisplatin compared with NCI-H292 and LC-AI cells. The resistance to cisplatin was significantly inhibited in A549 but not in NCI-H292 or LC-AI cells by knockdown of Nrf2 with its specific small interfering RNA (Nrf2-siRNA). The cell proliferation was also most prominently inhibited in A549 cells by treatment with Nrf2-siRNA. In A549 cells, the expression of self-defense genes, such as antioxidant enzymes, phase II detoxifying enzymes, and drug efflux pumps, was significantly reduced by Nrf2-siRNA concomitant with a reduction of the cellular glutathione level. The degree of DNA crosslink and apoptosis after treatment with cisplatin was significantly elevated in A549 cells by Nrf2-siRNA. Knockdown of Nrf2 arrested the cell cycle at G(1) phase with a reduction of the phosphorylated form of retinoblastoma protein in A549 and NCI-H292 cells but not in LC-AI cells. CONCLUSION:These results indicate that the Nrf2 system is essential for both cancer cell proliferation and resistance to anticancer drugs. Thus, Nrf2 might be a potential target to enhance the effect of anticancer drugs. |
| 巻・号 | 15(10) |
| ページ | 3423-32 |
| 公開日 | 2009-5-15 |
| DOI | 10.1158/1078-0432.CCR-08-2822 |
| PII | 1078-0432.CCR-08-2822 |
| PMID | 19417020 |
| MeSH | Antineoplastic Agents / pharmacology* Apoptosis / drug effects Bleomycin / pharmacology Cell Cycle / drug effects Cell Line, Tumor Cell Proliferation / drug effects* Cell Survival / drug effects Cisplatin / pharmacology Cyclin-Dependent Kinase Inhibitor p21 / metabolism Dose-Response Relationship, Drug Drug Resistance, Neoplasm* Flow Cytometry Fluorouracil / pharmacology Humans Immunoblotting Lung Neoplasms / genetics Lung Neoplasms / metabolism Lung Neoplasms / pathology Models, Biological NF-E2-Related Factor 2 / genetics NF-E2-Related Factor 2 / metabolism NF-E2-Related Factor 2 / physiology* RNA, Small Interfering / genetics Retinoblastoma Protein / metabolism Transfection |
| IF | 10.107 |
| 引用数 | 272 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | A549(RCB0098) RERF-LC-AI(RCB0444) |