Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States.
Proteomics and Metabolomics Core Facility, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States.
Elife. 2019 May 20;8:e45572. doi: 10.7554/eLife.45572.
NRF2 is emerging as a major regulator of cellular metabolism. However, most studies have been performed in cancer cells, where co-occurring mutations and tumor selective pressures complicate the influence of NRF2 on metabolism. Here we use genetically engineered, non-transformed primary murine cells to isolate the most immediate effects of NRF2 on cellular metabolism. We find that NRF2 promotes the accumulation of intracellular cysteine and engages the cysteine homeostatic control mechanism mediated by cysteine dioxygenase 1 (CDO1), which catalyzes the irreversible metabolism of cysteine to cysteine sulfinic acid (CSA). Notably, is preferentially silenced by promoter methylation in human non-small cell lung cancers (NSCLC) harboring mutations in KEAP1, the negative regulator of NRF2. CDO1 silencing promotes proliferation of NSCLC by limiting the futile metabolism of cysteine to the wasteful and toxic byproducts CSA and sulfite (SO), and depletion of cellular NADPH. Thus, CDO1 is a metabolic liability for NSCLC cells with high intracellular cysteine, particularly NRF2/KEAP1 mutant cells.
NRF2 正在成为细胞代谢的主要调节剂。然而，大多数研究都是在癌细胞中进行的，在这些细胞中，同时发生的突变和肿瘤选择压力使 NRF2 对代谢的影响变得复杂。在这里，我们使用基因工程的、非转化的原代鼠细胞来分离 NRF2 对细胞代谢的最直接影响。我们发现 NRF2 促进细胞内半胱氨酸的积累，并参与由半胱氨酸双加氧酶 1（CDO1）介导的半胱氨酸稳态控制机制，该机制催化半胱氨酸不可逆地代谢为半胱氨酸亚磺酸（CSA）。值得注意的是，在 KEAP1 （NRF2 的负调节剂）发生突变的人类非小细胞肺癌（NSCLC）中， 通过启动子甲基化而优先沉默。CDO1 的沉默通过限制半胱氨酸的无效代谢为浪费和有毒的副产物 CSA 和亚硫酸盐（SO）以及细胞 NADPH 的消耗来促进 NSCLC 的增殖。因此，CDO1 是高细胞内半胱氨酸的 NSCLC 细胞的代谢负担，特别是 NRF2/KEAP1 突变细胞的代谢负担。
