Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin
Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin
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DOI：
10.1016/j.lungcan.2007.09.021
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发表时间：
2008-04-01
期刊：
影响因子：
5.3
通讯作者：
Park, Raekil
中科院分区：
文献类型：
--
作者：
Kim, Hak-Ryul;Kim, Sejin;Park, Raekil
血红素氧合酶-1（HO-1）在多种肿瘤组织中高度表达，通过抗氧化和抗凋亡作用在肿瘤细胞生长中起重要作用。在此，我们证明了A549细胞表达高水平的HO-1，Nrf`2，和NF-κ B相比，其他肺癌细胞系，包括H23，H157，和H460。HO-1小干扰RNA（siRNA）的异位表达增加了细胞凋亡和procaspase-3的降解。用特异性针对Nrf 2和NF-κ B的siRNA转染研究揭示，A549细胞中HO-1的表达是由Nrf 2的转录激活介导的，而不是NF-κ B。A549细胞对顺铂细胞毒性的敏感性低于其他肺癌细胞系，伴随着HO-1表达和MAPK磷酸化以时间依赖性方式增加。此外，通过siRNA和特异性HO-1抑制剂ZnPP抑制HO-1增强顺铂对A549细胞的细胞毒性。HO-1活性的药理学抑制导致顺铂处理的细胞中ROS产生显著增加。此外，MAPK的药理学抑制剂抑制顺铂诱导HO-1和Nrf 2的表达。这些结果表明HO-1可能通过MAPK-Nrf 2途径调节肺癌A549细胞对顺铂的化疗敏感性。(C)2007爱思唯尔爱尔兰有限公司保留所有权利。
Heme oxygenase-1 (HO-1) is highly expressed in various tumor tissues and plays an important rote in tumor cell growth through anti-oxidative and anti-apoptotic effects. Herein, we demonstrate that A549 cells express high levels of HO-1, Nrf`2, and NF-kappa B compared to other lung cancer cell lines, including H23, H157, and H460. Ectopic expression of HO-1 small interfering RNA (siRNA) increased both apoptosis and degradation of procaspase-3. Transfection studies with siRNA specific for Nrf2 and NF-kappa B revealed that HO-1 expression in A549 cells is mediated by transcriptional activation of Nrf2, but not NF-kappa B. A549 cells are less susceptible to cisplatin cytotoxicity than other lung cancer cell lines, concomitant with increases in HO-1 expression and MAPK phosphorylation in a time-dependent fashion. Furthermore, inhibition of HO-1 by siRNA and a specific HO-1 inhibitor ZnPP augments cisplatin cytotoxicity toward A549 cells. Pharmacologic suppression of HO-1 activity resulted in a marked increase in the ROS generation in cisplatin-treated cells. In addition, pharmacologic inhibitors of MAPK suppressed the induction of HO-1 and Nrf2 expression by cisplatin. These findings suggest that HO-1 may modulate the chemosensitivity of lung cancer A549 cells to cisplatin through the MAPK-Nrf2 pathway. (C) 2007 Elsevier Ireland Ltd. All rights reserved.