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|Abstract:||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.|
|Citation:||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, Kang, Sumin. (2018). The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer.. Molecular cell, 69 (1), 87 - 99.e7. doi:10.1016/j.molcel.2017.11.025|
|Pages:||87 - 99.e7|
|Type of Material:||Journal Article|
|Journal/Proceeding Title:||Molecular Cell|
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