Okazaki Keito, Papagiannakopoulos Thales, Motohashi Hozumi
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.
Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA.
Biophys Rev. 2020 Apr;12(2):435-441. doi: 10.1007/s12551-020-00659-8. Epub 2020 Feb 28.
The KEAP1-NRF2 system is a sulfur-employing defense mechanism against oxidative and electrophilic stress. NRF2 is a potent transcription activator for genes mediating sulfur-involving redox reactions, and KEAP1 controls the NRF2 activity in response to the stimuli by utilizing reactivity of sulfur atoms. In many human cancer cells, the KEAP1-mediated regulation of NRF2 activity is abrogated, resulting in the persistent activation of NRF2. Persistently activated NRF2 drives malignant progression of cancers by increasing therapeutic resistance and promoting aggressive tumorigenesis, a state termed as NRF2 addiction. In NRF2-addicted cancer cell, NRF2 contributes to metabolic reprogramming in cooperation with other oncogenic pathways. In particular, NRF2 strongly activates cystine uptake coupled with glutamate excretion and glutathione synthesis, which increases consumption of intracellular glutamate. Decreased availability of glutamate limits anaplerosis of the TCA cycle, resulting in low mitochondrial respiration, and nitrogen source, resulting in the high dependency on exogenous non-essential amino acids. The highly enhanced glutathione synthesis is also likely to alter sulfur metabolism, which can contribute to the maintenance of the mitochondrial membrane potential in normal cells. The potent antioxidant and detoxification capacity supported by abundant production of glutathione is achieved at the expense of central carbon metabolism and requires skewed metabolic flow of sulfur. These metabolic features of NRF2 addiction status provide clues for novel therapeutic strategies to target NRF2-addicted cancer cells.
KEAP1-NRF2系统是一种利用硫元素的抗氧化和抗亲电应激防御机制。NRF2是介导含硫氧化还原反应的基因的强效转录激活因子，而KEAP1通过利用硫原子的反应性来响应刺激，从而控制NRF2的活性。在许多人类癌细胞中，KEAP1介导的NRF2活性调节被破坏，导致NRF2持续激活。持续激活的NRF2通过增加治疗抗性和促进侵袭性肿瘤发生来驱动癌症的恶性进展，这种状态被称为NRF2成瘾。在NRF2成瘾的癌细胞中，NRF2与其他致癌途径协同作用，促进代谢重编程。特别是，NRF2强烈激活胱氨酸摄取并伴有谷氨酸排泄和谷胱甘肽合成，这增加了细胞内谷氨酸的消耗。谷氨酸可用性的降低限制了三羧酸循环的回补反应，导致线粒体呼吸作用降低，以及氮源减少，导致对外源非必需氨基酸的高度依赖。高度增强的谷胱甘肽合成也可能改变硫代谢，这有助于维持正常细胞中的线粒体膜电位。谷胱甘肽的大量产生所支持的强大抗氧化和解毒能力是以牺牲中心碳代谢为代价实现的，并且需要硫的代谢流倾斜。NRF2成瘾状态的这些代谢特征为靶向NRF2成瘾癌细胞的新型治疗策略提供了线索。
