Nrf2 activation does not affect adenoma development in a mouse model of colorectal cancer.
Nrf2 activation does not affect adenoma development in a mouse model of colorectal cancer.
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DOI：
10.1038/s42003-021-02552-w
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发表时间：
2021-09-15
影响因子：
5.9
通讯作者：
Dinkova-Kostova AT
中科院分区：
文献类型：
--
作者：
Knatko EV;Castro C;Higgins M;Zhang Y;Honda T;Henderson CJ;Wolf CR;Griffin JL;Dinkova-Kostova AT
转录因子核因子红细胞2 p45相关因子2（Nrf 2）及其主要负调节因子Kelch样ECH相关蛋白1（Keap 1）位于氧化还原和中间代谢之间的界面。nrf 2激活在人类疾病模型中具有保护作用，并在临床试验中具有益处。因此，Keap 1/Nrf 2蛋白复合物是药物靶标。然而，在癌症中，Nrf 2起着双重作用，引起了人们对Nrf 2激活剂可能促进早期肿瘤生长的担忧。为了解决这个问题，我们研究了Nrf 2在结直肠腺瘤的发展中的作用，采用遗传学，药理学和代谢组学的方法。我们发现，在Gstp−/−：ApcMin/+小鼠中形成的结直肠腺瘤的特征是改变了一碳代谢，并且基因激活，而不是Nrf 2的破坏，增强了这些代谢改变。然而，与肿瘤和肿瘤周围组织之间的代谢差异的大小相比，这种增强是适度的，这表明Nrf 2激活所赋予的代谢变化可能对癌发生的早期阶段几乎没有贡献。事实上，在该模型中，无论是遗传（通过Keap 1敲低）还是药理学Nrf 2激活，也无论是其破坏，都不会影响结直肠腺瘤的形成。我们得出结论，药理学Nrf 2激活不太可能影响结直肠癌发展的早期阶段。Knatko等人通过进行遗传和药理学分析，研究了Nrf 2活性在结直肠腺瘤发生中的重要性。作者发现Keap 1敲低和Nrf 2激活影响非肿瘤结肠的代谢，但不影响该模型中结直肠腺瘤的形成。
Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator, Kelch-like ECH associated protein 1 (Keap1), are at the interface between redox and intermediary metabolism. Nrf2 activation is protective in models of human disease and has benefits in clinical trials. Consequently, the Keap1/Nrf2 protein complex is a drug target. However, in cancer Nrf2 plays a dual role, raising concerns that Nrf2 activators may promote growth of early neoplasms. To address this concern, we examined the role of Nrf2 in development of colorectal adenomas by employing genetic, pharmacological, and metabolomic approaches. We found that colorectal adenomas that form in Gstp−/−: ApcMin/+ mice are characterized by altered one-carbon metabolism and that genetic activation, but not disruption of Nrf2, enhances these metabolic alterations. However, this enhancement is modest compared to the magnitude of metabolic differences between tumor and peri-tumoral tissues, suggesting that the metabolic changes conferred by Nrf2 activation may have little contribution to the early stages of carcinogenesis. Indeed, neither genetic (by Keap1 knockdown) nor pharmacological Nrf2 activation, nor its disruption, affected colorectal adenoma formation in this model. We conclude that pharmacological Nrf2 activation is unlikely to impact the early stages of development of colorectal cancer. Knatko et al. examined the importance of Nrf2 activity in the development of colorectal adenomas by performing genetic and pharmacological analyses. The authors found that Keap1 knockdown and Nrf2 activation impacted the metabolism of the non-tumoral colon, but did not affect colorectal adenoma formation in this model.
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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：
3.8
作者：
Hanada N;Takahata T;Zhou Q;Ye X;Sun R;Itoh J;Ishiguro A;Kijima H;Mimura J;Itoh K;Fukuda S;Saijo Y
通讯作者：
Saijo Y
影响因子：
3.5
作者：
Carvalho, Andreia Neves;Marques, Carla;Gama, Maria Joao
通讯作者：
Gama, Maria Joao
影响因子：
7.3
作者：
Honda, Tadashi;Yoshizawa, Hidenori;Sundararajan, Chitra;David, Emilie;Lajoie, Marc J.;Favaloro, Frank G., Jr.;Janosik, Tomasz;Su, Xiaobo;Honda, Yukiko;Roebuck, Bill D.;Gribble, Gordon W.
通讯作者：
Gribble, Gordon W.
影响因子：
6.2
作者：
Allocati N;Masulli M;Di Ilio C;Federici L
通讯作者：
Federici L