Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth
Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth
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DOI：
10.1158/0008-5472.can-07-5003
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发表时间：
2008-03-01
期刊：
影响因子：
11.2
通讯作者：
Hirohashi, Setsuo
中科院分区：
文献类型：
--
作者：
Ohta, Tsutonm;Iijima, Kumiko;Hirohashi, Setsuo
氧化和亲电应激是由Keap1感受的，它通过调节药物代谢和抗氧化应激酶/蛋白的表达来激活Nrf2以实现细胞保护。由于氧化和亲电应激导致许多疾病，包括癌症，我们假设NRF2-Keap1系统的异常可能促进癌细胞的生长。我们对65例日本肺癌患者的Keap1基因进行了测序，发现了5个非同义体细胞突变，突变频率为8%。我们还鉴定了两个非同义的体细胞Keap1基因突变和两个低水平表达Keap1的肺癌细胞株。在肺癌细胞中，低Keap1活性(由于突变或低水平表达)导致Nrf2的核定位和结构性激活。后者导致编码多药耐药泵、11期解毒酶和抗氧化性应激酶/蛋白的细胞保护基因的结构性表达。肺癌细胞中这些靶基因的上调导致顺铂耐药。NRF2的激活也刺激了低水平表达Keap1的肺癌衍生细胞系、突变细胞系和在稳态条件下表达Keap1的小鼠胚胎成纤维细胞的生长。因此，抑制NRF2可能为激活NRF2的肺癌提供新的治疗途径。
Oxidative and electrophilic stresses are sensed by Keap1, which activates Nrf2 to achieve cytoprotection by regulating the expression of drug-metabolizing and antioxidative stress enzymes/proteins. Because oxidative and electrophilic stresses cause many diseases, including cancer, we hypothesized that an abnormality in the Nrf2-Keap1 system may facilitate the growth of cancer cells. We sequenced the KEAP1 gene of 65 Japanese patients with lung cancer and identified five nonsynonymous somatic mutations at a frequency of 8%. We also identified two nonsynonymous somatic KEAP1 gene mutations and two lung cancer cell lines expressing KEAP1 at reduced levels. In lung cancer cells, low Keap1 activity (due to mutations or low-level expression) led to nuclear localization and constitutive activation of Nrf2. The latter resulted in constitutive expression of cytoprotective genes encoding multidrug resistance pumps, phase 11 detoxifying enzymes, and antioxidative stress enzymes/proteins. Up-regulation of these target genes in lung cancer cells led to cisplatin resistance. Nrf2 activation also stimulated growth of lung cancer-derived cell lines expressing KEAP1 at low levels and in mutant cell lines and in Keap1-mill mouse embryonic fibroblasts under homeostatic conditions. Thus, inhibition of NRF2 may provide new therapeutic approaches in lung cancers with activation of Nrf2.