High glucose drives non-small cell lung cancer progression via OGT-mediated O-GlcNAcylation and PI3K/AKT/mTOR pathway activation.
- 1Department of Cardiothoracic Surgery, Tianjin Medical University General Hospital, Tianjin, China.
- 2Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
Abstract
Hyperglycemia is an independent risk factor for poor prognosis in non-small cell lung cancer (NSCLC), yet the underlying metabolic-oncogenic crosstalk remains incompletely defined. The hexosamine biosynthetic pathway (HBP) senses glucose flux and generates UDP-GlcNAc for O-GlcNAcylation, a post-translational modification catalyzed by O-GlcNAc transferase (OGT). Here we investigate whether and how high glucose exploits OGT-mediated O-GlcNAcylation to fuel NSCLC malignancy. A549 and H1299 NSCLC cells were cultured in normal (5.5 mM) or high (25 mM) glucose. Proliferation, colony formation, migration, invasion, wound healing, and apoptosis were evaluated. OGT and global O-GlcNAc levels were assessed in tumor versus adjacent normal tissues by immunohistochemistry and in cells by western blotting. Stable OGT-knockdown (sh-OGT) lines were generated to dissect functional requirements. PI3K/AKT/mTOR pathway activation was examined by phospho-specific western blotting. The cell lines were tested and confirmed to be mycoplasma-free. High glucose significantly enhanced proliferation, clonogenicity, migration, and invasion, and suppressed apoptosis by downregulating Bax and upregulating Bcl-2. OGT and global O-GlcNAcylation were markedly upregulated in NSCLC tissues and in high-glucose-treated cells. OGT silencing abrogated high-glucose-induced malignant phenotypes, restored apoptotic sensitivity, and reverted the Bax/Bcl-2 ratio. Mechanistically, high-glucose-driven O-GlcNAcylation activated PI3K, AKT, and mTOR phosphorylation, whereas OGT knockdown blunted this activation. OGT-orchestrated hyper-O-GlcNAcylation is a pivotal conduit linking the hyperglycemic microenvironment to PI3K/AKT/mTOR-dependent NSCLC progression. Targeting OGT-mediated O-GlcNAcylation may offer a precision therapeutic strategy for NSCLC patients with comorbid diabetes or hyperglycemia.
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BibTeX
@article{shi2026high,
title = {{High glucose drives non-small cell lung cancer progression via OGT-mediated O-GlcNAcylation and PI3K/AKT/mTOR pathway activation.}},
author = {Guo-Dong Shi and Hui-Jiang Gao and Dong Wang and Yu-Cheng Wei and Peng Zhang},
journal = {Translational cancer research},
year = {2026},
month = sep,
doi = {10.21037/tcr-2026-2076},
url = {https://europepmc.org/article/MED/42997903},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - High glucose drives non-small cell lung cancer progression via OGT-mediated O-GlcNAcylation and PI3K/AKT/mTOR pathway activation.
AU - Guo-Dong Shi
AU - Hui-Jiang Gao
AU - Dong Wang
AU - Yu-Cheng Wei
AU - Peng Zhang
PY - 2026
DA - 2026/09/28
JO - Translational cancer research
DO - 10.21037/tcr-2026-2076
UR - https://europepmc.org/article/MED/42997903
AB - Hyperglycemia is an independent risk factor for poor prognosis in non-small cell lung cancer (NSCLC), yet the underlying metabolic-oncogenic crosstalk remains incompletely defined. The hexosamine biosynthetic pathway (HBP) senses glucose flux and generates UDP-GlcNAc for O-GlcNAcylation, a post-translational modification catalyzed by O-GlcNAc transferase (OGT). Here we investigate whether and how high glucose exploits OGT-mediated O-GlcNAcylation to fuel NSCLC malignancy. A549 and H1299 NSCLC cells were cultured in normal (5.5 mM) or high (25 mM) glucose. Proliferation, colony formation, migration, invasion, wound healing, and apoptosis were evaluated. OGT and global O-GlcNAc levels were assessed in tumor versus adjacent normal tissues by immunohistochemistry and in cells by western blotting. Stable OGT-knockdown (sh-OGT) lines were generated to dissect functional requirements. PI3K/AKT/mTOR pathway activation was examined by phospho-specific western blotting. The cell lines were tested and confirmed to be mycoplasma-free. High glucose significantly enhanced proliferation, clonogenicity, migration, and invasion, and suppressed apoptosis by downregulating Bax and upregulating Bcl-2. OGT and global O-GlcNAcylation were markedly upregulated in NSCLC tissues and in high-glucose-treated cells. OGT silencing abrogated high-glucose-induced malignant phenotypes, restored apoptotic sensitivity, and reverted the Bax/Bcl-2 ratio. Mechanistically, high-glucose-driven O-GlcNAcylation activated PI3K, AKT, and mTOR phosphorylation, whereas OGT knockdown blunted this activation. OGT-orchestrated hyper-O-GlcNAcylation is a pivotal conduit linking the hyperglycemic microenvironment to PI3K/AKT/mTOR-dependent NSCLC progression. Targeting OGT-mediated O-GlcNAcylation may offer a precision therapeutic strategy for NSCLC patients with comorbid diabetes or hyperglycemia.
SN - 2218-676X
SN - 2219-6803
ER -