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

TitleThe PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer.
Publication TypeJournal Article
Year of Publication2018
AuthorsJin, L, Chun, J, Pan, C, Kumar, A, Zhang, G, Ha, Y, Li, D, Alesi, GN, Kang, Y, Zhou, L, Yu, W-M, Magliocca, KR, Khuri, FR, Qu, C-K, Metallo, C, Owonikoko, TK, Kang, S
JournalMol Cell
Volume69
Issue1
Pagination87-99.e7
Date Published2018 01 04
ISSN1097-4164
KeywordsA549 Cells, AMP-Activated Protein Kinases, Animals, Anoikis, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Cell Line, Tumor, DNA-Binding Proteins, Enzyme Activation, Female, Glutamate Dehydrogenase, HEK293 Cells, Humans, Lung Neoplasms, Mice, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Neoplasm Metastasis, Neoplasm Transplantation, Protein-Serine-Threonine Kinases, Small Cell Lung Carcinoma, Transplantation, Heterologous
Abstract

<p>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.</p>

DOI10.1016/j.molcel.2017.11.025
Alternate JournalMol Cell
PubMed ID29249655
PubMed Central IDPMC5777230
Grant ListR01 CA175316 / CA / NCI NIH HHS / United States
R01 CA188652 / CA / NCI NIH HHS / United States
R01 CA207768 / CA / NCI NIH HHS / United States