The KEAP1-NRF2 System in Cancer.
The KEAP1-NRF2 System in Cancer.
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DOI：
10.3389/fonc.2017.00085
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发表时间：
2017
影响因子：
4.7
通讯作者：
Yamamoto M
中科院分区：
文献类型：
--
作者：
Taguchi K;Yamamoto M
癌细胞首先适应微环境，然后增殖。肿瘤抑制基因或癌基因的突变经常在癌细胞中发现。全面的基因组分析已发现各种癌症中 KEAP1 或 NRF2 基因以及众所周知的肿瘤抑制基因或癌基因（如 TP53、CDKN2A、PTEN 和 PIK3CA）的体细胞突变和其他改变。癌细胞中 NRF2 的异常激活是通过 KEAP1 或 NRF2 基因的体细胞突变以及破坏 KEAP1 与 NRF2 结合的其他机制发生的。不受调控的 NRF2 赋予癌细胞对抗癌药物和活性氧 (ROS) 的高水平抵抗力，并引导癌细胞进行代谢重编程。因此，NRF2已被研究作为癌症的治疗靶分子。已使用两种策略通过治疗药物靶向 NRF2：抑制 NRF2 和诱导 NRF2。 NRF2抑制剂可能有效对抗NRF2成瘾的癌细胞，其中NRF2被异常激活。这些抑制剂尚未被确定为用于治疗人类癌症的 NRF2 靶向抗癌药物。 NRF2 激活的诊断可以促进 NRF2 抑制剂用于治疗 NRF2 成瘾癌症患者。相反，NRF2诱导剂已被用于或正在开发用于非癌症疾病。此外，NRF2诱导剂与传统抗癌药物甚至NRF2抑制剂联合可用于癌症化疗。
Cancer cells first adapt to the microenvironment and then propagate. Mutations in tumor suppressor genes or oncogenes are frequently found in cancer cells. Comprehensive genomic analyses have identified somatic mutations and other alterations in the KEAP1 or NRF2 genes and in well-known tumor suppressor genes or oncogenes, such as TP53, CDKN2A, PTEN, and PIK3CA, in various types of cancer. Aberrant NRF2 activation in cancer cells occurs through somatic mutations in the KEAP1 or NRF2 gene as well as through other mechanisms that disrupt the binding of KEAP1 to NRF2. Unregulated NRF2 confers on cancer cells high-level resistance to anticancer drugs and reactive oxygen species (ROS) and directs cancer cells toward metabolic reprogramming. Therefore, NRF2 has been studied as a therapeutic target molecule in cancer. Two strategies have been used to target NRF2 via therapeutic drugs: inhibition of NRF2 and induction of NRF2. NRF2 inhibitors may be effective against NRF2-addicted cancer cells in which NRF2 is aberrantly activated. These inhibitors have not yet been established as NRF2-targeted anticancer drugs for the treatment of human cancers. Diagnosis of NRF2 activation could facilitate the use of NRF2 inhibitors for the treatment of patients with NRF2-addicted cancers. Conversely, NRF2 inducers have been used or are being developed for non-cancer diseases. In addition, NRF2 inducers may be useful for cancer chemotherapy in combination with conventional anticancer agents or even NRF2 inhibitors.