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由NRF2/G6PD通过葡萄糖代谢重编程诱导的减少压力促进了暴露于酸盐的人类角质细胞的恶性转变
Qianlei Yang1, Rui Yan1, Jie Zhang1
1Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, Jiangsu, People's Republic of China.
核因子E2相关因子2 (NRF2) 激活在人类角质细胞 (HaCaT细胞) 中,通过重编程葡萄糖代谢和诱导减小压力,特别是通过增加NRF2/葡萄糖-6-酸盐脱酶 (G6PD) 来驱动恶性转变.
科学领域:
- 细胞生物学 细胞生物学
- 癌症研究 癌症研究
- 生物化学 生物化学
背景情况:
- 之前的研究表明,核因子-E2相关因子2 (NRF2) 在由甲 (NaAsO2) 诱导的人类角质细胞 (HaCaT细胞) 恶性转变期间持续激活.
- 在这种恶性转变过程中NRF2的确切作用尚不清楚.
研究的目的:
- 研究NRF2在矿诱导的HaCaT细胞恶性转化中的作用.
- 阐明在这个过程中涉及氧化还原平衡和葡萄糖代谢的机制.
主要方法:
- 用NaAsO2对HaCaT细胞和Mito-Grx1-roGFP2HaCaT细胞进行治疗,以诱导恶性转变并评估线粒体谷氨水平.
- 在各种通道上测量了氧化还原水平,葡萄糖代谢指标 (例如,葡萄糖-6-酸盐,乳酸盐,乙-CoA) 和葡萄糖代谢酶表达.
- 使用siRNA进行NRF2和葡萄糖-6-酸盐脱酶 (G6PD) 沉默,以评估它们对细胞氧化还原状态和恶性表型的影响.
主要成果:
- 石治疗的早期阶段显示氧化压力增加,NRF2激活持续,细胞/线粒体还原性压力升高 (GSH/GSSG,NADPH/NADP+).
- 后期阶段表现出增加的葡萄糖代谢指标和NRF2/G6PD表达,与降低的乙-CoA,表明代谢重编程.
- 沉默NRF2或G6PD逆转了葡萄糖代谢的变化,减少了还原性压力,并逆转了恶性表型.
结论:
- 酸盐诱导的恶性转变涉及氧化应激的初始阶段,随后是持续的NRF2激活.
- 在后期阶段,高水平的NRF2和G6PD促进葡萄糖代谢重编程,导致减少性压力和HaCaT细胞的恶性转变.
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