Nrf2 Enhances Cell Proliferation and Resistance to Anticancer Drugs in Human Lung Cancer
Nrf2 Enhances Cell Proliferation and Resistance to Anticancer Drugs in Human Lung Cancer
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DOI：
10.1158/1078-0432.ccr-08-2822
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发表时间：
2009-05-15
影响因子：
11.5
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Homma, Shinsuke;Ishii, Yukio;Yamamoto, Masayuki
目的：NF-E2相关因子2（Nrf2）是抗氧化和解毒酶的关键转录调节因子，在癌细胞中大量表达。实验设计：我们使用了三种具有不同程度Nrf2激活的人肺癌细胞系：Nrf2在A549细胞中高度激活，在NCI-H292细胞中轻度激活，而在LC-Al细胞中在未刺激条件下不激活。A549细胞对顺铂的耐药性高于NCI-H292和LC-Al细胞。用特异性小干扰RNA（Nrf2-siRNA）敲低Nrf2基因可显著抑制A549细胞对顺铂的耐药性，但对NCI-H292或LC-Al细胞的耐药性无明显影响。用Nrf2-siRNA处理A549细胞也最显著地抑制细胞增殖。在A549细胞中，自我防御基因的表达，如抗氧化酶，第二阶段解毒酶，和药物外排泵，显着减少Nrf2-siRNA伴随着细胞谷胱甘肽水平的降低。Nrf2-siRNA可显著增加顺铂处理后A549细胞DNA交联和凋亡的程度。敲低Nrf2可使A549和NCI-H292细胞的细胞周期停滞在G_1期，并使视网膜母细胞瘤蛋白磷酸化形式减少，但在LC-A1细胞中无此作用。因此，Nrf2可能是一个潜在的靶点，以提高抗癌药物的效果。
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-Al cells under unstimulated conditions.Result: A549 cells showed higher resistance to cisplatin compared with NCI-H292 and LC-Al cells. The resistance to cisplatin was significantly inhibited in A549 but not in NCI-H292 or LC-Al 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, phase with a reduction of the phosphorylated form of retinoblastoma protein in A549 and NCI-H292 cells but not in LC-Al 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.