Inhibition of heme oxygenase-1 with an epidermal growth factor receptor inhibitor and cisplatin decreases proliferation of lung cancer A549 cells
Inhibition of heme oxygenase-1 with an epidermal growth factor receptor inhibitor and cisplatin decreases proliferation of lung cancer A549 cells
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DOI：
10.1016/j.lungcan.2009.03.015
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发表时间：
2010-01-01
期刊：
影响因子：
5.3
通讯作者：
Ishigatsubo, Yoshiaki
中科院分区：
文献类型：
--
作者：
Kuroda, Hideyo;Takeno, Mitsuhiro;Ishigatsubo, Yoshiaki
血红素加氧酶-1 (HO-1) 由多种应激刺激和许多抗肿瘤药物诱导。我们研究了 HO-1 在人肺上皮腺癌细胞系 A549（组成型表达 HO-1）中对顺铂化疗耐药的参与。我们发现顺铂治疗进一步增强了 HO-1 的表达，这与表皮生长因子受体 (EGFR) 介导的信号通路的激活以及随后的 NF-kappa B 核转位有关。与研究结果一致，使用 EGFR 选择性酪氨酸激酶抑制剂 (AG1478) 或 Akt 抑制剂治疗会干扰 EGFR 后信号通路， 抑制顺铂诱导的 HO-1 表达。虽然单独使用 AG1478 或 HO-1 siRNA 不会改变 A549 细胞的细胞活力，但这两种药物均显着增强顺铂的细胞毒性。在大细胞癌细胞系H460中也发现了类似的数据。总的来说，结果表明 A549 细胞对顺铂的耐药性通过 EGFR 介导的信号通路（包括 PI3k/Akt 和 NF-kappa B 系统的激活）与 HO-1 相关。我们的数据还表明，EGFR 选择性酪氨酸激酶抑制剂和 Akt 抑制剂可恢复 A549 细胞对顺铂的化学敏感性。 (C) 2009 年，爱思唯尔爱尔兰有限公司出版。
Heme oxygenase-1 (HO-1) is induced by a variety of stress stimuli and by many antitumor agents. We investigated involvement of HO-1 in chemoresistance of cisplatin in human lung epithelial adenocarcinoma cell line, A549, which constitutively expressed HO-1. We found that treatment with cisplatin further augmented HO-1 expression, which was associated with activation of the epidermal growth factor receptor (EGFR) mediated signaling pathway and subsequent nuclear translocation of NF-kappa B. In concordance with the findings, treatment with EGFR-selective tyrosine kinase inhibitor (AG1478) or an Akt inhibitor, which interfere with the post-EGFR signaling pathway, suppressed cisplatin induced HO-1 expression. While either AG1478 or HO-1 siRNA alone did not alter cell viability of A549 cells, both agents significantly augmented cytotoxicity of cisplatin. The similar data also found in large cell carcinoma cell line, H460. Collectively, the results indicate that resistance to cisplatin in A549 cells is associated with HO-1 through EGFR mediated signaling pathway including activation of the PI3k/Akt and NF-kappa B systems. Our data also suggest that the chemosensitivity of A549 cells to cisplatin is restored by EGFR-selective tyrosine kinase inhibitor and an Akt inhibitor. (C) 2009 Published by Elsevier Ireland Ltd.