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

2023; Cell Press; Volume: 35; Issue: 3 Linguagem: Inglês

10.1016/j.cmet.2023.01.012

1932-7420

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 Vornbäumen, Benedikt R. Dürr, Mariko Takahashi, Marianne Richter, Junbing Zhang, Tzu-yi Yang, Vindhya Vijay, David E. Fisher, Aaron N. Hata, Marcia C. Haigis, Raúl Mostoslavsky, Nabeel Bardeesy, Thales Papagiannakopoulos, Liron Bar‐Peled,

MicroRNA in disease regulation

Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation 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 that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.