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The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer
Molecular Cell ( IF 16.0 ) Pub Date : 2017-12-14 , DOI: 10.1016/j.molcel.2017.11.025
Lingtao Jin , Jaemoo Chun , Chaoyun Pan , Avi Kumar , Guojing Zhang , Youna Ha , Dan Li , Gina N. Alesi , Yibin Kang , Lu Zhou , Wen-Mei Yu , Kelly R. Magliocca , Fadlo R. Khuri , Cheng-Kui Qu , Christian Metallo , Taofeek K. Owonikoko , Sumin Kang

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.



中文翻译:

PLAG1-GDH1轴通过LKK1缺陷型肺癌的CamKK2-AMPK信号促进神经过敏和肿瘤转移。

LKB1的丢失与肺癌的转移增加和预后不良有关,但靶向药物的开发尚处于婴儿期。在这里,我们报告的谷氨酰胺分解酶,谷氨酸脱氢酶1(GDH1),通过多形性腺瘤基因1(PLAG1)分离后上调,在LKB1缺陷型肺癌中提供了抗厌氧反应和促转移信号。从机制上讲,GDH1产物α-KG通过增强底物AMPK的结合来激活CamKK2,这有助于产生产生耐阳极氧化作用的能量。GDH1对AMPK的作用在LKB1缺陷型肺癌中很明显,其中AMPK激活主要取决于CamKK2。在患者衍生的异种移植模型中以R162靶向GDH1可以减轻肿瘤转移,在肺癌患者中进行相关性研究进一步验证了我们发现的临床意义。

更新日期:2017-12-14
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