Title | The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Jin, 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 |
Journal | Mol Cell |
Volume | 69 |
Issue | 1 |
Pagination | 87-99.e7 |
Date Published | 2018 Jan 04 |
ISSN | 1097-4164 |
Keywords | A549 Cells, AMP-Activated Protein Kinase Kinases, 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> |
DOI | 10.1016/j.molcel.2017.11.025 |
Alternate Journal | Mol Cell |
PubMed ID | 29249655 |
PubMed Central ID | PMC5777230 |
Grant List | R01 CA175316 / CA / NCI NIH HHS / United States R01 CA188652 / CA / NCI NIH HHS / United States R01 CA207768 / CA / NCI NIH HHS / United States |