Seng Seyha, Avraham Hava Karsenty, Jiang Shuxian, Yang Suping, Sekine Masayuki, Kimelman Noam, Li Huchun, Avraham Shalom
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Cancer Res. 2007 Sep 15;67(18):8596-604. doi: 10.1158/0008-5472.CAN-06-3785.
The transcription factor NF-E2-related factor 2 (Nrf2) translocates into the nucleus and activates phase II genes encoding detoxification enzymes and antioxidant proteins, resulting in the protection of cells from oxidative insults. However, the involvement of Nrf2-mediated oxidative stress responses in breast cancer cells is largely unknown. Notably, during our study of the Nrf2 pathway in breast cancer cells, we observed that the nuclear matrix protein NRP/B was expressed and colocalized with Nrf2 in these cells, suggesting that NRP/B is involved in Nrf2-mediated oxidative stress responses. The expression level of NRP/B was variable in different breast cancer cells and breast cancer tissues, and was found to be localized in the nucleus. NRP/B expression was increased after exposure to the oxidative stress agent, hydrogen peroxide (H(2)O(2)), particularly in the highly aggressive MDA-MB-231 breast cancer cells. Association of NRP/B with Nrf2 in vitro and in vivo was observed in MDA-MB-231 breast cancer cells, and this association was up-regulated upon exposure to H(2)O(2), but not to sodium nitroprusside, SIN-1, and DETA-NO. NRP/B also enhanced Nrf2-mediated NAD(P)H:quinine oxidoreductase 1 promoter activity. Thus, this study reveals that NRP/B enhances oxidative stress responses in breast cancer cells via the Nrf2 pathway, identifying a novel role of nuclear matrix protein(s) in oxidative stress responses.
转录因子NF-E2相关因子2（Nrf2）转位至细胞核并激活编码解毒酶和抗氧化蛋白的II期基因，从而保护细胞免受氧化损伤。然而，Nrf2介导的氧化应激反应在乳腺癌细胞中的作用在很大程度上尚不清楚。值得注意的是，在我们对乳腺癌细胞中Nrf2途径的研究中，我们观察到核基质蛋白NRP/B在这些细胞中表达并与Nrf2共定位，这表明NRP/B参与了Nrf2介导的氧化应激反应。NRP/B的表达水平在不同的乳腺癌细胞和乳腺癌组织中存在差异，并且发现其定位于细胞核。暴露于氧化应激剂过氧化氢（H₂O₂）后，NRP/B的表达增加，尤其是在侵袭性很强的MDA-MB-231乳腺癌细胞中。在MDA-MB-231乳腺癌细胞中观察到NRP/B与Nrf2在体外和体内的结合，并且这种结合在暴露于H₂O₂后上调，但在暴露于硝普钠、SIN-1和DETA-NO后未上调。NRP/B还增强了Nrf2介导的NAD(P)H：醌氧化还原酶1启动子活性。因此，本研究揭示NRP/B通过Nrf2途径增强乳腺癌细胞中的氧化应激反应，确定了核基质蛋白在氧化应激反应中的新作用。
