Multidrug-resistant protein-3 gene regulation by the transcription factor Nrf2 in human bronchial epithelial and non-small-cell lung carcinoma.
Multidrug-resistant protein-3 gene regulation by the transcription factor Nrf2 in human bronchial epithelial and non-small-cell lung carcinoma.
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DOI：
10.1016/j.freeradbiomed.2009.03.023
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发表时间：
2009-06-15
影响因子：
7.4
通讯作者：
Forman, Henry Jay
中科院分区：
文献类型：
--
作者：
Mahaffey, Christopher M.;Zhang, Hongqiao;Rinna, Alessandra;Holland, William;Mack, Philip C.;Forman, Henry Jay
关键词：
多药耐药蛋白(MRP)是ATP结合盒超家族的成员，通过将包括化疗药物在内的有毒化合物输送到细胞外来促进解毒。化疗、放疗和其他异物应激已被证明可增加特定MRP的水平，尽管其潜在的机制在很大程度上仍不清楚。此外，MRP3被怀疑在非小细胞肺癌(NSCLC)的耐药中起作用。对MRP3启动子的分析表明，存在多个假定的电泳式反应元件(EpRE)，这些序列表明该基因可能受到与EPRE结合的关键转录因子Nrf2的调控。这项研究的目的是确定MRP3的诱导是否依赖于转录因子Nrf2。Keap1是Nrf2的关键调节因子，它将Nrf2隔离在细胞质中，阻止Nrf2进入细胞核。亲电性脂质过氧化产物4-羟基-2-壬烯醛(HNE)被证明可以修饰Keap1，使Nrf2进入细胞核。我们发现，在野生型Keap1的细胞系(人支气管上皮细胞系HBE1和非小细胞肺癌细胞系H358)中，HNE上调MRP3的mRNA和蛋白水平，而在Keap1突变的非小细胞肺癌细胞系(A549和H460)中不上调MRP3的mRNA和蛋白水平。带有突变型Keap1的细胞系具有结构性更高的MRP3，而HNE处理并不会增加MRP3。在HBE1细胞中，用siRNA沉默Nrf2抑制了MRP3和HNE的诱导。最后，我们发现沉默Nrf2也增加了顺铂对H358细胞的毒性。因此，联合结果支持了HNE诱导MRP3涉及Nrf2激活的假设。
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.
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影响因子：
5.3
作者：
Itoh, K;Mochizuki, M;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
DOI：
10.1093/jnci/90.22.1735
发表时间：
1998-11-18
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Belinsky, MG;Bain, LJ;Kruh, GD
通讯作者：
Kruh, GD
影响因子：
6.1
作者：
Gradhand, Ulrike;Tegude, Heike;Koening, Joerg
通讯作者：
Koening, Joerg
影响因子：
4.8
作者：
Alam, J;Stewart, D;Cook, JL
通讯作者：
Cook, JL