NRF2 regulates the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via FOCAD-FAK signaling pathway
NRF2 regulates the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via FOCAD-FAK signaling pathway
复制标题
NRF2通过FOCAD-FAK信号通路调节人NSCLC细胞对胱氨酸剥夺诱导的铁死亡的敏感性
DOI：
10.1016/j.redox.2020.101702
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发表时间：
2020-10-01
期刊：
影响因子：
11.4
通讯作者：
Feng, Yetong
中科院分区：
文献类型：
--
作者：
Liu, Pengfei;Wu, Di;Feng, Yetong
Transcription factor nuclear factor-erythroid 2-like 2 (NRF2) mainly regulates cellular antioxidant response, redox homeostasis and metabolic balance. Our previous study illustrated the translational significance of NRF2-mediated transcriptional repression, and the transcription of FOCAD gene might be negatively regulated by NRF2. However, the detailed mechanism and the related significance remain unclear. In this study, we mainly explored the effect of NRF2-FOCAD signaling pathway on ferroptosis regulation in human non-small-cell lung carcinoma (NSCLC) model. Our results confirmed the negative regulation relationship between NRF2 and FOCAD, which was dependent on NRF2-Replication Protein Al (RPA1)-Antioxidant Response Elements (ARE) complex. In addition, FOCAD promoted the activity of focal adhesion kinase (FAK), which further enhanced the sensitivity of NSCLC cells to cysteine deprivation-induced ferroptosis via promoting the tricarboxylic acid (TCA) cycle and the activity of Complex I in mitochondrial electron transport chain (ETC). However, FOCAD didn't affect GPX4 inhibition-induced ferroptosis. Moreover, the treatment with the combination of NRF2 inhibitor (brusatol) and erastin showed better therapeutic action against NSCLC in vitro and in vivo than single treatment, and the improved therapeutic function partially depended on the activation of FOCAD-FAK signal. Taken together, our study indicates the close association of NRF2-FOCAD-FAK signaling pathway with cysteine deprivation-induced ferroptosis, and elucidates a novel insight into the ferroptosis-based therapeutic approach for the patients with NSCLC.
