PCK2 Promotes Malignant Phenotypes of Non-Small Cell Lung Cancer Cells via SLC38A2-Mediated Glutamine Uptake

Libo RUAN; Kewang XU; Minjun ZHAO; Fan ZHANG; Wenjun ZENG; Haiyan ZHANG

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Article Navigation > Journal of Kunming Medical University > 2026 > Accepted Manuscript

Libo RUAN, Kewang XU, Minjun ZHAO, Fan ZHANG, Wenjun ZENG, Haiyan ZHANG. PCK2 Promotes Malignant Phenotypes of Non-Small Cell Lung Cancer Cells via SLC38A2-Mediated Glutamine Uptake[J]. Journal of Kunming Medical University.

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PCK2 Promotes Malignant Phenotypes of Non-Small Cell Lung Cancer Cells via SLC38A2-Mediated Glutamine Uptake

1.
Department of Geriatric Medicine，The First People’s Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology，Kunming Yunnan 650032
2.
Department of Endocrinology，Shangrao Municipal Hospital，Shangrao Jiangxi 334000
3.
School of Medicine，Kunming University of Science and Technology，Kunming Yunnan 650032
4.
Health Management Center，The First People’s Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology，Kunming Yunnan 650032，China

Received Date: 2025-08-25

Abstract

Abstract

To investigate the molecular mechanism by which phosphoenolpyruvate carboxykinase 2 （PCK2） regulates glutamine transport under low-glucose conditions and its impact on the malignant behaviors of non-small cell lung cancer （NSCLC） cells. Methods: Stable PCK2 knockdown （KD group） and negative control （NC group） cell lines （n = 3 for all experiments） were established in the human NSCLC A549 cell line.. The impact of PCK2 on the transcription and protein expression of solute carrier family 38 member 2 （SLC38A2） were assessed using PRM proteomics, Western blotting, and dual-luciferase reporter assays. Cell proliferation （MTT）, migration （wound healing）, and apoptosis （flow cytometry） were analyzed via MTT assay, scratch wound healing assay, and flow cytometry, respectively under low-glucose conditions （1000 mg/L）. Functional rescue experiments were performed by establishing a Gln supplementation group （KD+Gln group） and an SLC38A2 overexpression group （KD+SLC38A2 group）. Results: Upon PCK2 knockdown, SLC38A2 promoter activity decreased by approximately 60% （P < 0.0001） and its protein expression was significantly reduced （P < 0.01）. Under low-glucose conditions, cell proliferation was inhibited in the KD group. The 24-hour migration rate （≈20%） was significantly lower than that in the NC group （≈55%, P < 0.0001）, while the apoptosis rate （≈13%） was significantly higher （NC group ≈4.5%, P < 0.0001）. Both glutamine supplementation and SLC38A2 overexpression significantly reversed these phenomena, restoring migration rates to approximately 50% （P < 0.01 vs. KD） and reducing apoptosis to about 5.5% （P < 0.0001 vs. KD）. Conclusion: Under low-glucose stress, PCK2 maintains Gln uptake by regulating SLC38A2 expression at the transcriptional level, thereby promoting the proliferation, migration, and survival of NSCLC cells. The PCK2-SLC38A2 axis unveils a novel mechanism in tumor metabolic reprogramming and may represent a potential therapeutic target for NSCLC.
- Non-small cell lung cancer （NSCLC）,
- PCK2,
- SLC38A2,
- Glutamine transport,
- Low glucose

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