1. The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer.
- Author
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Jin, Lingtao, Chun, Jaemoo, Pan, Chaoyun, Kumar, Avi, Zhang, Guojing, Ha, Youna, Li, Dan, Alesi, Gina N., Kang, Yibin, Zhou, Lu, Yu, Wen-Mei, Magliocca, Kelly R., Khuri, Fadlo R., Qu, Cheng-Kui, Metallo, Christian, Owonikoko, Taofeek K., and Kang, Sumin
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LUNG cancer , *CANCER prognosis , *ANOIKIS , *METASTASIS , *CELL communication , *GLUTAMATE dehydrogenase - Abstract
Summary 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. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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