Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer.
Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer.
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激活的氨基酸反应途径通过重编程非小细胞肺癌中的谷氨酰胺代谢产生阿帕替尼耐药
DOI：
10.1038/s41419-022-05079-y
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发表时间：
2022-07-21
影响因子：
9
通讯作者：
Wu, Gang
中科院分区：
文献类型：
--
作者：
Zhou, Xiaoshu;Zhou, Rui;Rao, Xinrui;Hong, Jiaxin;Li, Qianwen;Jie, Xiaohua;Wang, Jian;Xu, Yingzhuo;Zhu, Kuikui;Li, Zhenyu;Wu, Gang
阿帕替尼治疗实体瘤（包括非小细胞肺癌（NSCLC））的疗效已得到证实。然而，阿帕替尼介导的肿瘤致死的直接功能机制和耐药的精确机制在很大程度上是未知的。在这项研究中，我们证明阿帕替尼可以通过氨基酸代谢失衡的机制重新编程人NSCLC中的谷氨酰胺代谢。阿帕替尼抑制了谷氨酰胺催化剂的起始酶和限速酶GLS 1的表达。然而，代谢平衡的破坏导致氨基酸反应（AAR）途径的激活，称为GCN 2/eIF 2 α/ATF 4途径。此外，ATF 4的激活负责诱导SLC 1A 5和ASNS，从而促进谷氨酰胺的消耗和代谢。有趣的是，阿帕替尼和ATF 4沉默的组合消除了NSCLC细胞中的谷氨酰胺代谢。此外，ATF 4的敲低增强了阿帕替尼在体外和体内的抗肿瘤作用。总之，本研究表明，阿帕替尼可通过激活人NSCLC细胞中的AAR途径重新编程谷氨酰胺代谢，并表明靶向ATF 4是缓解阿帕替尼耐药的潜在治疗策略。
The efficacy of apatinib has been confirmed in the treatment of solid tumors, including non-small-cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by apatinib and the precise mechanisms of drug resistance are largely unknown. In this study, we demonstrated that apatinib could reprogram glutamine metabolism in human NSCLC via a mechanism involved in amino acid metabolic imbalances. Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2α/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells. Moreover, knockdown of ATF4 enhanced the antitumor effect of apatinib both in vitro and in vivo. In summary, this study showed that apatinib could reprogram glutamine metabolism through the activation of the AAR pathway in human NSCLC cells and indicated that targeting ATF4 is a potential therapeutic strategy for relieving apatinib resistance.
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靶向 KDM4C 通过激活肺癌趋化因子 CXCL10 转录增强 CD8 T 细胞介导的抗肿瘤免疫
影响因子：
10.9
作者：
Jie X;Chen Y;Zhao Y;Yang X;Xu Y;Wang J;Meng R;Zhang S;Dong X;Zhang T;Yang K;Xu S;Wu G
通讯作者：
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影响因子：
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作者：
Miranda-Gonçalves V;Cardoso-Carneiro D;Valbom I;Cury FP;Silva VA;Granja S;Reis RM;Baltazar F;Martinho O
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Martinho O
DOI：
10.1007/978-3-030-74180-8_1
发表时间：
2021-01-01
期刊：
AMINO ACIDS IN NUTRITION AND HEALTH: AMINO ACIDS IN GENE EXPRESSION, METABOLIC REGULATION, AND EXERCISING PERFORMANCE
影响因子：
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作者：
Sah, Nirvay;Wu, Guoyao;Bazer, Fuller W.
通讯作者：
Bazer, Fuller W.
影响因子：
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作者：
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Savaskan N
影响因子：
9
作者：
Liu K;Ren T;Huang Y;Sun K;Bao X;Wang S;Zheng B;Guo W
通讯作者：
Guo W