Abstract
PLAG1-mediated GDH1 upregulation promotes LKB1-deficient lung cancer anoikis resistance.
Major finding: PLAG1-mediated GDH1 upregulation promotes LKB1-deficient lung cancer anoikis resistance.
Mechanism: In the absence of LKB1, the GDH1 product α-KG mediates the activation of AMPK by CAMKK2.
Impact: Targeting the PLAG1–GDH1 axis may be a potential therapeutic strategy to prevent metastasis.
Loss of liver kinase B1 (LKB1, encoded by STK11), which regulates the activation of the metabolic regulator AMPK, is associated with increased metastasis and decreased survival in patients with lung cancer. To elucidate the mechanism underlying the prometastatic role of altered tumor metabolism in lung cancer, Jin and colleagues interrogated the glutaminolysis pathway, which promotes tumor growth and metastasis. The glutaminolytic enzyme glutamate dehydrogenase 1 (GDH1) was shown to confer anoikis resistance, which is required for metastasis, in LKB1-deficient lung cancer cell lines. The transcription factor pleomorphic adenoma gene 1 (PLAG1) was upregulated during anoikis resistance and transactivated the GDH1 promoter; PLAG1 knockdown decreased GDH1 expression and increased anoikis. Knockdown of GDH1 sensitized LKB1-deficient, but not LKB1-proficient, cells to anoikis induction in vitro and reduced the metastatic potential of LKB1-deficient cells in vivo, whereas the GDH1 product α-KG restored anoikis resistance in GDH1-depleted LKB1-deficient cells, suggesting that both GDH1 and α-KG promote anoikis resistance. Similarly, treatment of LKB1-null cells with a small-molecule inhibitor of GDH1 rescued anoikis in vitro and attenuated the metastatic potential of LKB1-deficient cell lines and patient-derived xenografts in vivo. Further, GDH1 knockdown resulted in decreased activation of AMPK and its upstream activator calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), which were rescued by the addition of α-KG, and diminished cellular ATP levels. CAMKK2 knockdown resulted in the loss of AMPK activation and anoikis resistance in LKB1-deficient cells; conversely, CAMKK2 overexpression restored anoikis resistance and AMPK activation in GDH1-knockdown cells. Mechanistically, α-KG promoted CAMKK2 activation by enhancing the interaction between CAMKK2 and its substrate AMPKα. Consistent with these findings, GDH1 signaling was correlated with metastasis in human LKB1-deficient lung cancers. These results describe the mechanism by which glutaminolysis promotes metastasis and suggest that GDH1 may be a potential antimetastatic target.
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