KEAP1 deficiency drives glucose dependency and sensitizes lung cancer cells and tumors to GLUT inhibition.
KEAP1 deficiency drives glucose dependency and sensitizes lung cancer cells and tumors to GLUT inhibition.
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DOI：
10.1016/j.isci.2021.102649
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发表时间：
2021-06-25
期刊：
影响因子：
5.8
通讯作者：
Gan B
中科院分区：
文献类型：
--
作者：
Koppula P;Olszewski K;Zhang Y;Kondiparthi L;Liu X;Lei G;Das M;Fang B;Poyurovsky MV;Gan B
癌细胞中的代谢重编程可以产生代谢负债。KEAP 1突变型肺癌对目前大多数疗法都是难治的。在这里，我们表明，KEAP 1缺陷促进肺癌细胞的葡萄糖依赖性，KEAP 1突变/缺陷型肺癌细胞比WT细胞更容易受到葡萄糖剥夺的影响。肺癌细胞中KEAP 1的失活诱导NRF 2转录因子的组成性激活和NRF 2靶向胱氨酸转运蛋白SLC 7A 11的异常表达;在葡萄糖限制下，KEAP 1失活的肺癌细胞中的高胱氨酸摄取刺激毒性细胞内二硫键积累、NADPH消耗和细胞死亡，其可通过NRF 2-SLC 7A 11轴的基因切除或抑制二硫键积累的治疗来挽救。最后，我们表明KEAP 1失活的肺癌细胞或异种移植肿瘤对葡萄糖转运蛋白抑制剂敏感。总之，我们的研究结果表明，KEAP 1缺陷诱导肺癌细胞的葡萄糖依赖性，并揭示了治疗相关的代谢倾向。突变型KEAP 1暴露由高胱氨酸摄取引起的代谢倾向KEAP 1-NRF 2-SLC 7A 11轴驱动葡萄糖依赖性KEAP 1突变型NSCLC肿瘤对GLUT抑制剂敏感生理学;细胞生物学;癌症
Metabolic reprogramming in cancer cells can create metabolic liabilities. KEAP1-mutant lung cancer is refractory to most current therapies. Here we show that KEAP1 deficiency promotes glucose dependency in lung cancer cells, and KEAP1-mutant/deficient lung cancer cells are more vulnerable to glucose deprivation than their WT counterparts. Mechanistically, KEAP1 inactivation in lung cancer cells induces constitutive activation of NRF2 transcription factor and aberrant expression of NRF2 target cystine transporter SLC7A11; under glucose limitation, high cystine uptake in KEAP1-inactivated lung cancer cells stimulates toxic intracellular disulfide buildup, NADPH depletion, and cell death, which can be rescued by genetic ablation of NRF2-SLC7A11 axis or treatments inhibiting disulfide accumulation. Finally, we show that KEAP1-inactivated lung cancer cells or xenograft tumors are sensitive to glucose transporter inhibitor. Together, our results reveal that KEAP1 deficiency induces glucose dependency in lung cancer cells and uncover a therapeutically relevant metabolic liability. Mutant KEAP1 exposes a metabolic liability provoked by high cystine uptake KEAP1-NRF2-SLC7A11 axis drives glucose dependency KEAP1 mutant NSCLC tumors are sensitive to GLUT inhibitor Physiology; Cell biology; Cancer
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影响因子：
11.2
作者：
Galan-Cobo, Ana;Sitthideatphaiboon, Piyada;Heymach, John, V
通讯作者：
Heymach, John, V
同时发生的基因组改变对KRAS突变非小细胞肺癌患者结局的影响。
DOI：
10.1158/1078-0432.ccr-17-1841
发表时间：
2018-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arbour KC;Jordan E;Kim HR;Dienstag J;Yu HA;Sanchez-Vega F;Lito P;Berger M;Solit DB;Hellmann M;Kris MG;Rudin CM;Ni A;Arcila M;Ladanyi M;Riely GJ
通讯作者：
Riely GJ
影响因子：
8
作者：
Lei G;Zhang Y;Hong T;Zhang X;Liu X;Mao C;Yan Y;Koppula P;Cheng W;Sood AK;Liu J;Gan B
通讯作者：
Gan B
影响因子：
7.7
作者：
Krail, Elsa B.;Wang, Belinda;Hahn, William C.
通讯作者：
Hahn, William C.
DOI：
10.1096/fj.201801225r
发表时间：
2019-03
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Chauhan AS;Liu X;Jing J;Lee H;Yadav RK;Liu J;Zhou Y;Gan B
通讯作者：
Gan B