PCK2 Promotes Non-Small Cell Lung Cancer Progression via SLC38A2- Mediated Glutamine Uptake and mTORC1 Activation

Phosphoenolpyruvate carboxykinase 2 (PCK2) contributes to cancer metabolic adaptation, yet its role in glutamine (Gln) transport and downstream signaling in non-small cell lung cancer (NSCLC) under glucose deprivation is unclear. This study aimed to investigate the PCK2-SLC38A2-mTORC1 axis in NSCLC under metabolic stress.

A549 NSCLC cells were subjected to PCK2 knockdown using shRNA. Glutamine transporter expression was assessed via PRM proteomics and Western blot. Proliferation, migration, apoptosis, mTORC1 activity, and autophagy were analyzed under low-glucose conditions. Rescue assays were performed using Gln supplementation or SLC38A2 overexpression. Expression of PCK2 and SLC38A2 was evaluated in NSCLC tissues using immunohistochemistry.

PCK2 knockdown reduced Gln transporter levels, especially SLC38A2, and impaired cell proliferation and migration, while inducing apoptosis under low-glucose conditions. These effects were reversed by Gln supplementation or SLC38A2 overexpression. Mechanistically, PCK2 knockdown suppressed mTORC1 signaling and disrupted autophagy flux, both of which were restored by SLC38A2. Clinically, high expression of PCK2 and SLC38A2 was observed in NSCLC tissues and correlated with poor prognosis. Experimental results from both NSCLC patient-derived samples and tissue models demonstrated that downregulation of PCK2 effectively attenuated the progression of non-small cell lung cancer.

PCK2 promoted NSCLC cell survival and progression by maintaining Gln uptake through SLC38A2, thereby activating mTORC1 and modulating autophagy. These findings support a metabolic adaptation mechanism critical to tumor aggressiveness.

The PCK2-SLC38A2-mTORC1 signaling axis sustains NSCLC cell viability under glucose limitation and represents a potential metabolic vulnerability for therapeutic targeting.