Targeting NRF2 signaling for cancer chemoprevention.
Targeting NRF2 signaling for cancer chemoprevention.
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DOI：
10.1016/j.taap.2009.08.028
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发表时间：
2010-04-01
影响因子：
3.8
通讯作者：
Kensler TW
中科院分区：
文献类型：
--
作者：
Kwak MK;Kensler TW
通过诱导细胞保护酶来调节致癌物的代谢和处置是预防癌症的几种有前途的策略之一。诱导剂如二硫硫代硫酮和萝卜硫素的化学预防功效已经在动物和人类中进行了广泛的研究。KEAP 1-NRF 2系统是这些化学预防剂的关键但不是单方面的分子靶标。转录因子NRF 2（NF-E2相关因子2）是一个基因亚组表达的主要调节因子，其产生负责亲电体和活性氧的解毒以及去除或修复它们的一些损伤产物的蛋白质。据信，化学预防性酶诱导剂通过介导KEAP 1蛋白的构象变化或激活靶向KEAP 1-NRF 2复合物的磷酸化级联来影响KEAP 1和NRF 2之间的相互作用。这些事件反过来影响NRF 2的稳定性和贩运。最近的进展阐明了KEAP 1-NRF 2信号传导的基础结构生物学以及NRF 2转录控制下的基因簇的鉴定，有助于了解NRF 2激活剂的潜在多效性作用，并发现新型有效的化学预防剂，例如三萜类化合物。尽管适当地存在关于KEAP 1-NRF 2系统在癌细胞生物学中的有害作用的担忧，特别是当该途径影响细胞存活和耐药性时，但NRF 2激活剂作为化学预防剂的开发和使用仍然具有保护正常细胞免受多种环境应激的巨大希望，所述环境应激有助于癌症和其他慢性退行性疾病的负担。
Modulation of the metabolism and disposition of carcinogens through induction of cytoprotective enzymes is one of several promising strategies to prevent cancer. Chemopreventive efficacies of inducers such as dithiolethiones and sulforaphane have been extensively studied in animals as well as in humans. The KEAP1-NRF2 system is a key, but not unilateral, molecular target for these chemopreventive agents. The transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of the expression of a subset of genes, which produce proteins responsible for the detoxication of electrophiles and reactive oxygen species as well as the removal or repair of some of their damage products. It is believed that chemopreventive enzyme inducers affect the interaction between KEAP1 and NRF2 through either mediating conformational changes of the KEAP1 protein or activating phosphorylation cascades targeting the KEAP1-NRF2 complex. These events in turn affect NRF2 stability and trafficking. Recent advances elucidating the underlying structural biology of KEAP1-NRF2 signaling and identification of the gene clusters under the transcriptional control of NRF2 are facilitating understanding of the potential pleiotropic effects of NRF2 activators and discovery of novel classes of potent chemopreventive agents such as the triterpenoids. Although there is, appropriately a concern regarding a deleterious role of the KEAP1-NRF2 system in cancer cell biology, especially as the pathway affects cell survival and drug resistance, the development and the use of NRF2 activators as chemopreventive agents still holds a great promise for protection of normal cells from a diversity of environmental stresses that contribute to the burden of cancer and other chronic, degenerative diseases.
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DOI：
10.1073/pnas.172398899
发表时间：
2002-09-03
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Holtzclaw, WD;Talalay, P
通讯作者：
Talalay, P
DOI：
10.1073/pnas.0500815102
发表时间：
2005-03-22
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Liby, KT;Talalay, P
通讯作者：
Talalay, P
影响因子：
4.1
作者：
Balogun, E;Hoque, M;Motterlini, R
通讯作者：
Motterlini, R
影响因子：
9.7
作者：
Cho, Jeong-Min;Manandhar, Sarala;Kwak, Mi-Kyoung
通讯作者：
Kwak, Mi-Kyoung
影响因子：
3.8
作者：
Aoki, Y;Sato, H;Yamamoto, M
通讯作者：
Yamamoto, M