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

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. [Display omitted] •GDH1 contributes to anoikis resistance and tumor metastasis by activating CamKK2•α-KG binds to CamKK2 and recruits AMPK to CamKK2•In LKB1 null lung cancer, GDH1-induced CamKK2 substitutes for LKB1 to activate AMPK•PLAG1 induces GDH1 expression upon cell detachment from the matrix Although elevated glutaminolysis has been demonstrated in cancer cells, the precise mechanism by which glutaminolysis promotes tumor metastasis remains unclear. In this article, Jin et al. demonstrate a mechanism by which GDH1 provides anti-anoikis and pro-metastatic signals through activating CamKK2 and AMPK that promotes tumor metastasis in LKB1-deficient lung cancer.