Signaling and Targeting of Glutamate Dehydrogenase 1 in Metastatic Non-Small Cell Lung Carcinoma
Technical Report,01 Sep 2017,31 Aug 2018
Emory University Atlanta United States
Pagination or Media Count:
Loss of LKB1 is associated with increased metastasis and poor prognosis in non-small cell lung carcinoma NSCLC, which is about 30 percent NSCLC patients, but the development of targeted agents is in its infancy. During this grant funding period Sept 1, 2017-Sept 28, 2018, we identified that a glutaminolytic enzyme glutamate dehydrogenase 1 GDH1 that converts glutamate to alpha-ketoglutarate a-KG is upregulated upon detachment via pleomorphic adenoma gene 1 PLAG1, and provides anti-anoikis and pro-metastatic signals in LKB1-deficient NSCLC. Mechanistically, the GDH1 product a-KG activates calciumcalmodulin dependent protein kinase kinase 2 CamKK2 by enhancing its substrate 5AMP-activated protein kinase AMPK binding, which contributes to energy production that confers anoikis resistance and tumor metastasis. The effect of GDH1 on AMPK is evident in LKB1-deficient NSCLC, 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 using TCGA database and immunohistochemistry staining of paired primary and metastasized tumor specimens further validated the clinical relevance of this 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 NSCLC.
- Medicine and Medical Research