The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer

• DOI: 10.1016/j.molcel.2017.11.025
• Publication Date: 2017-12-14T16:35:46Z
• Authors: 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
• Keywords: Anoikis; Pterostilbene

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.