小柯机器人

美国马萨诸塞州总医院Liron Bar-Peled等研究人员合作发现，NRF2的激活诱导NADH还原应激并为肺癌提供代谢上的弱点。相关论文于2023年2月24日在线发表在《细胞—代谢》杂志上。

据研究人员介绍，多种癌症通过激活转录因子NFR2的负调控因子KEAP1突变来调节氧化应激。NRF2在KEAP1突变型癌症中已被广泛研究；然而，这一途径在野生型KEAP1癌症中的作用仍然知之甚少。

为了回答这个问题，研究人员人员在50多种非小细胞肺癌细胞系中通过药物失活KEAP1诱导NRF2。出乎意料的是，在13%的细胞系中观察到活力的显著下降——这一效应被NRF2去除所挽救。全基因组和靶向CRISPR筛选显示，NRF2通过上调NAD⁺消耗酶ALDH3A1诱导NADH还原应激。通过这些发现，研究人员发现用KEAP1抑制剂或内源性KEAP1突变处理的细胞选择性地容易受到复合物I抑制，这损害了NADH氧化能力并增强了还原性应激。因此，研究人员确定还原应激是NRF2激活型肺癌的代谢易感性。

附：英文原文

Title: NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer

Author: Tommy Weiss-Sadan, Maolin Ge, Makiko Hayashi, Magdy Gohar, Cong-Hui Yao, Adriaan de Groot, Stefan Harry, Alexander Carlin, Hannah Fischer, Lei Shi, Ting-Yu Wei, Charles H. Adelmann, Konstantin Wolf, Tristan Vornbumen, Benedikt R. Dürr, Mariko Takahashi, Marianne Richter, Junbing Zhang, Tzu-Yi Yang, Vindhya Vijay, David E. Fisher, Aaron N. Hata, Marcia C. Haigis, Raul Mostoslavsky, Nabeel Bardeesy, Thales Papagiannakopoulos, Liron Bar-Peled

Issue&Volume: 2023-02-24

Abstract: Multiple cancers regulate oxidative stress by activating the transcription factorNRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensivelyin KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1remains poorly understood. To answer this question, we induced NRF2 via pharmacologicalinactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly,marked decreases in viability were observed in >13% of the cell lines—an effect thatwas rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed thatNRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated withKEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADHoxidation capacity and potentiates reductive stress. Thus, we identify reductive stressas a metabolic vulnerability in NRF2-activated lung cancers.

DOI: 10.1016/j.cmet.2023.01.012

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00012-8

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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