Tobacco Smoking Rewires Cell Metabolism by Inducing GAPDH Succinylation to Promote Lung Cancer Progression.
Patient behavior and physiology can directly affect cancer metabolism. Smoking is the leading risk factor for non-small cell lung cancer (NSCLC). In this study, we identified that smoking modulates lung cancer cell metabolism through altered protein post-translational modification. Proteomic analyses identified elevated K251 succinylation (K251-Su) of GAPDH, a key enzyme ... in glycolysis, in NSCLC samples, and GAPDH K251-Su was significantly higher in patients who smoke compared with nonsmokers. Exposure of lung cancer cells to cigarette smoke extract led to increased uptake of glutamine and enhanced GAPDH K251-Su. Glutamine uptake by cancer cells in hypoxic and nutrient-deficient microenvironments provided succinyl-CoA donors for GAPDH succinylation at K251, which was catalyzed by acyltransferase p300. K251-Su increased GAPDH stability by suppressing TRIM4-mediated K254 ubiquitination. GAPDH K251-Su enhanced glycolysis and glutamine reductive carboxylation to meet the demands for cell growth and to support survival in hypoxic and nutrient-depleted conditions, promoting tumor growth and metastasis. These findings indicate that tobacco smoking mediates metabolic reprogramming of cancer cells through succinylation of GAPDH to drive NSCLC progression.Smoking-induced GAPDH succinylation coordinates glycolysis and glutamine metabolism and supports lung cancer cell survival in stressful microenvironments to promote tumor progression, highlighting quitting smoking as a potential strategy to target cancer metabolism.
Mesh Terms:
Animals, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Disease Progression, Female, Glutamine, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Glyceraldehyde-3-Phosphate Dehydrogenases, Glycolysis, Humans, Lung Neoplasms, Male, Mice, Mice, Nude, Protein Processing, Post-Translational, Tobacco Smoking, Tumor Microenvironment, Ubiquitination
Animals, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Disease Progression, Female, Glutamine, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Glyceraldehyde-3-Phosphate Dehydrogenases, Glycolysis, Humans, Lung Neoplasms, Male, Mice, Mice, Nude, Protein Processing, Post-Translational, Tobacco Smoking, Tumor Microenvironment, Ubiquitination
Cancer Res
Date: Aug. 01, 2025
PubMed ID: 40366632
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