The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer.
The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer.
复制标题
PLAG1-GDH1轴通过LKB1缺陷型肺癌中的CAMKK2-AMPK信号传导促进厌食症和肿瘤转移。
DOI：
10.1016/j.molcel.2017.11.025
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发表时间：
2018-01-04
期刊：
影响因子：
16
通讯作者：
Kang S
中科院分区：
文献类型：
--
作者：
Jin L;Chun J;Pan C;Kumar A;Zhang G;Ha Y;Li D;Alesi GN;Kang Y;Zhou L;Yu WM;Magliocca KR;Khuri FR;Qu CK;Metallo C;Owonikoko TK;Kang S
LKB1的缺失与肺癌转移增加和预后不良相关，但靶向药物的开发尚处于起步阶段。在这里，我们报道了一种谷氨酰胺水解酶谷氨酸脱氢酶1 (GDH1)，在多形性腺瘤基因1 （PLAG1）脱离后上调，在lkb1缺失的肺癌中提供抗肿瘤和促转移信号。从机制上说，GDH1产物α-KG通过增强其底物AMPK的结合来激活CamKK2，这有助于能量的产生，从而获得抗氧化性。GDH1对AMPK的影响在lkb1缺乏的肺癌中是明显的，其中AMPK的激活主要依赖于CamKK2。以GDH1为靶点的R162在患者来源的异种移植瘤模型和肺癌患者的相关研究中减弱肿瘤转移，进一步验证了我们的发现的临床相关性。我们的研究揭示了gdh1介导的谷氨酰胺解代谢重编程介导肺癌转移的分子机制，并为lkb1缺陷肺癌患者提供了治疗策略。
Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents is in its infancy. Here we report that a glutaminolytic enzyme glutamate dehydrogenase 1 (GDH1), upregulated upon detachment via pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product α-KG activates CamKK2 by enhancing its substrate AMPK binding, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with R162 attenuated tumor metastasis in patient-derived xenograft model and correlation studies in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis and offers a therapeutic strategy for patients with LKB1-deficient lung cancer.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
21.3
作者：
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影响因子：
64.8
作者：
Jiang L;Shestov AA;Swain P;Yang C;Parker SJ;Wang QA;Terada LS;Adams ND;McCabe MT;Pietrak B;Schmidt S;Metallo CM;Dranka BP;Schwartz B;DeBerardinis RJ
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DeBerardinis RJ
影响因子：
8
作者：
Alesi GN;Jin L;Li D;Magliocca KR;Kang Y;Chen ZG;Shin DM;Khuri FR;Kang S
通讯作者：
Kang S
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.