NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis.
NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis.
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DOI：
10.3390/cancers12123609
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发表时间：
2020-12-02
期刊：
影响因子：
5.2
通讯作者：
Hayes JD
中科院分区：
文献类型：
--
作者：
Robertson H;Dinkova-Kostova AT;Hayes JD
转录因子NRF2控制抗氧化和解毒基因的表达。正常情况下，NRF2的活性在细胞内受到严格控制，并不断调整，以确保细胞免受内源性化学物质和环境因子的干扰，这些化学物质和环境因子扰乱了细胞内抗氧化/促氧化平衡（即氧化还原），而细胞内抗氧化/促氧化平衡是细胞生长和生存所必需的。这种对NRF2的严格控制是由一种叫做KEAP1的抑制蛋白实现的，这种抑制蛋白在正常条件下永久地以NRF2蛋白为目标，使其降解，但当受到氧化剂或硫醇反应性化学物质的挑战时，就无法做到这一点。在癌症的背景下，众所周知，刺激NRF2短期可逆激活的药物可以在有限的时间内提供保护，防止暴露于致癌化学物质。然而，人们也越来越普遍地认识到，NRF2的永久超激活是由编码NRF2的基因的体细胞突变或与NRF2降解相关的基因引起的，这在某些癌症中经常观察到，并与不良预后相关。在本文中，我们对描述NRF2对癌症发展的看似模糊的贡献的文献进行了批判性概述。特别是，我们描述了在肿瘤中负责NRF2上调的遗传和其他机制的范围，并强调了我们在不同类型癌症中发生频率的知识缺陷。此外，我们还讨论了NRF2的上调如何有助于肿瘤的生长和存活，特定类型癌症中NRF2的上调是否与特定癌基因的突变有关，以及这种情况可能发生在癌症发展的哪个阶段。最后，我们讨论了已经提出的治疗策略，选择性靶向NRF2永久激活的肿瘤，以克服NRF2相关的耐药性。NF-E2 p45相关因子2 （NRF2，在人体内由NFE2L2编码）介导对巯基反应性应激源的短期适应。在正常细胞中，巯基反应性应激源激活NRF2有助于在有限的时间内防止化学致癌物通过诱导编码药物代谢酶的基因引发癌症。然而，在许多肿瘤类型中，NRF2是永久上调的。在这种情况下，其过度表达的靶基因通过抑制氧化应激支持癌症的促进和进展，因为它们组成性地增加了清除活性氧（ROS）的能力，并通过增加核糖核苷酸合成、丝氨酸生物合成和自噬来支持细胞增殖。在这里，我们描述了癌症的化学预防和NRF2在协调防止化学致癌作用中所起的重要作用的发现。我们同样描述了NFE2L2和编码NRF2主要抑制因子kelch样ech相关蛋白1 （KEAP1）以及编码E3泛素连接酶复合物Cullin 3 （CUL3）成分的体细胞突变的发现，这些突变导致NRF2的永久激活，并认识到这种突变经常发生在许多类型的癌症中。值得注意的是，NFE2L2、KEAP1和CUL3中导致NRF2持续上调的突变通常与激活KRAS和PI3K-PKB/Akt通路的突变共存，这表明NRF2支持KRAS或PKB/Akt过度活跃的肿瘤的生长。除了体细胞突变外，NRF2在人类肿瘤中的激活还可以通过其他方式发生，例如选择性剪接导致NRF2蛋白缺乏keap1结合结构域或与NRF2竞争的其他keap1结合伙伴过表达。最后，由于NRF2上调与癌症化疗和放疗的耐药性有关，我们描述了可能用于抑制生长和克服NRF2过度活跃肿瘤的耐药性的策略。
Transcription factor NRF2 controls expression of antioxidant and detoxification genes. Normally, the activity of NRF2 is tightly controlled in the cell, and is continuously adjusted to ensure that cells are protected against endogenous chemicals and environmental agents that perturb the intracellular antioxidant/pro-oxidant balance (i.e., redox) that must be maintained for them to grow and survive in an appropriate manner. This tight control of NRF2 is achieved by a repressor protein called KEAP1 that perpetually targets NRF2 protein for degradation under normal conditions, but is unable to do so when challenged with oxidants or thiol-reactive chemicals. In the context of cancer, it is well known that drugs that stimulate short-term and reversible activation of NRF2 can provide protection for a limited period against exposure to chemicals that cause cancer. However, it is also becoming widely recognised that permanent hyper-activation of NRF2 resulting from somatic mutations in the gene that encodes NRF2, or in genes associated with its degradation, is frequently observed in certain cancers and associated with poor outcome. In this article, we provide a critical overview of the literature describing the seemingly ambiguous contributions that NRF2 makes to the development of cancer. In particular, we describe the range of genetic and other mechanisms that are responsible for the upregulation of NRF2 in tumours, and highlight shortcomings in our knowledge of how frequently this occurs in different types of cancer. Moreover, we discuss how upregulation of NRF2 might aid the growth and survival of tumours, whether NRF2 upregulation in particular types of cancer is associated with mutations in specific oncogenes, and at what stage of cancer development this is likely to occur. Lastly, we discuss therapeutic strategies that have been proposed that selectively target tumours in which NRF2 is permanently activated with a view to overcoming NRF2-associated drug resistance. NF-E2 p45-related factor 2 (NRF2, encoded in the human by NFE2L2) mediates short-term adaptation to thiol-reactive stressors. In normal cells, activation of NRF2 by a thiol-reactive stressor helps prevent, for a limited period of time, the initiation of cancer by chemical carcinogens through induction of genes encoding drug-metabolising enzymes. However, in many tumour types, NRF2 is permanently upregulated. In such cases, its overexpressed target genes support the promotion and progression of cancer by suppressing oxidative stress, because they constitutively increase the capacity to scavenge reactive oxygen species (ROS), and they support cell proliferation by increasing ribonucleotide synthesis, serine biosynthesis and autophagy. Herein, we describe cancer chemoprevention and the discovery of the essential role played by NRF2 in orchestrating protection against chemical carcinogenesis. We similarly describe the discoveries of somatic mutations in NFE2L2 and the gene encoding the principal NRF2 repressor, Kelch-like ECH-associated protein 1 (KEAP1) along with that encoding a component of the E3 ubiquitin-ligase complex Cullin 3 (CUL3), which result in permanent activation of NRF2, and the recognition that such mutations occur frequently in many types of cancer. Notably, mutations in NFE2L2, KEAP1 and CUL3 that cause persistent upregulation of NRF2 often co-exist with mutations that activate KRAS and the PI3K-PKB/Akt pathway, suggesting NRF2 supports growth of tumours in which KRAS or PKB/Akt are hyperactive. Besides somatic mutations, NRF2 activation in human tumours can occur by other means, such as alternative splicing that results in a NRF2 protein which lacks the KEAP1-binding domain or overexpression of other KEAP1-binding partners that compete with NRF2. Lastly, as NRF2 upregulation is associated with resistance to cancer chemotherapy and radiotherapy, we describe strategies that might be employed to suppress growth and overcome drug resistance in tumours with overactive NRF2.
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DOI：
10.1126/science.aaw9872
发表时间：
2020-04-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badgley MA;Kremer DM;Maurer HC;DelGiorno KE;Lee HJ;Purohit V;Sagalovskiy IR;Ma A;Kapilian J;Firl CEM;Decker AR;Sastra SA;Palermo CF;Andrade LR;Sajjakulnukit P;Zhang L;Tolstyka ZP;Hirschhorn T;Lamb C;Liu T;Gu W;Seeley ES;Stone E;Georgiou G;Manor U;Iuga A;Wahl GM;Stockwell BR;Lyssiotis CA;Olive KP
通讯作者：
Olive KP
同时发生的基因组改变对KRAS突变非小细胞肺癌患者结局的影响。
DOI：
10.1158/1078-0432.ccr-17-1841
发表时间：
2018-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arbour KC;Jordan E;Kim HR;Dienstag J;Yu HA;Sanchez-Vega F;Lito P;Berger M;Solit DB;Hellmann M;Kris MG;Rudin CM;Ni A;Arcila M;Ladanyi M;Riely GJ
通讯作者：
Riely GJ
影响因子：
16.6
作者：
Best, Sarah A.;Ding, Sheryl;Sutherland, Kate D.
通讯作者：
Sutherland, Kate D.
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
DOI：
10.1073/pnas.1305687110
发表时间：
2013-09-17
影响因子：
11.1
作者：
Baird, Liam;Lleres, David;Dinkova-Kostova, Albena T.
通讯作者：
Dinkova-Kostova, Albena T.