The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism.
The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism.
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DOI：
10.3389/fonc.2012.00200
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发表时间：
2012
影响因子：
4.7
通讯作者：
Yamamoto M
中科院分区：
文献类型：
--
作者：
Mitsuishi Y;Motohashi H;Yamamoto M
Keap 1-Nrf 2 [Kelch-like ECH-associated protein 1-nuclear factor（erythroid-derived 2）-like 2]途径在保护细胞免受氧化和外源性应激中起核心作用。Nrf 2是一种有效的转录激活因子，它识别一种独特的DNA序列，称为抗氧化反应元件（ARE）。在正常条件下，Nrf 2与细胞质中的Keap 1结合，导致蛋白酶体降解。暴露于亲电体或活性氧后，Nrf 2变得稳定，易位到细胞核中，并激活各种细胞保护基因的转录。Nrf 2在癌细胞中的作用受到越来越多的关注，因为在许多预后不良的人类癌症中观察到Nrf 2的组成性稳定。最近的研究表明，Nrf 2的抗氧化和解毒活性赋予癌细胞化学和放射抗性。在这篇综述中，我们提供了Keap 1-Nrf 2系统的概述，并讨论其在生理和病理条件下的作用，包括癌症。我们还介绍了我们最近的研究结果，描述了Nrf 2在癌细胞代谢中的功能。Nrf 2可能通过增强细胞保护和合成代谢为癌细胞提供生长优势。最后，我们讨论了Nrf 2抑制剂对癌症治疗的可能影响。
The Keap1–Nrf2 [Kelch-like ECH-associated protein 1–nuclear factor (erythroid-derived 2)-like 2] pathway plays a central role in the protection of cells against oxidative and xenobiotic stresses. Nrf2 is a potent transcription activator that recognizes a unique DNA sequence known as the antioxidant response element (ARE). Under normal conditions, Nrf2 binds to Keap1 in the cytoplasm, resulting in proteasomal degradation. Following exposure to electrophiles or reactive oxygen species, Nrf2 becomes stabilized, translocates into the nucleus, and activates the transcription of various cytoprotective genes. Increasing attention has been paid to the role of Nrf2 in cancer cells because the constitutive stabilization of Nrf2 has been observed in many human cancers with poor prognosis. Recent studies have shown that the antioxidant and detoxification activities of Nrf2 confer chemo- and radio-resistance to cancer cells. In this review, we provide an overview of the Keap1–Nrf2 system and discuss its role under physiological and pathological conditions, including cancers. We also introduce the results of our recent study describing Nrf2 function in the metabolism of cancer cells. Nrf2 likely confers a growth advantage to cancer cells through enhancing cytoprotection and anabolism. Finally, we discuss the possible impact of Nrf2 inhibitors on cancer therapy.