Wang Kun, Li Jingzhuo, Zhang Hai, Ma Hongyan, Cui Hong-Yong, Ju Huai-Qiang, Zhang Jing, Ma Qing-Zhi, Zhao Ming, Zeng Qing-Mei, Zou Jie, Sun Xiu-Xuan, Nan Gang, Qian Meirui, Jing Lin, Li Yiming, Xiong Cai-Feng, Yang Qiu-Zi, Wang Hao, Jiang Jian-Li, Chen Zhi-Nan, Chen Liang, Huang Wan
Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, China.
State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Xi'an, China.
Cancer Res. 2025 Aug 1;85(15):2838-2857. doi: 10.1158/0008-5472.CAN-24-3525.
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.
患者行为和生理状态可直接影响癌症代谢。吸烟是非小细胞肺癌（NSCLC）的主要危险因素。在本研究中，我们发现吸烟通过改变蛋白质翻译后修饰来调节肺癌细胞代谢。蛋白质组学分析确定，在NSCLC样本中，糖酵解关键酶甘油醛-3-磷酸脱氢酶（GAPDH）的K251琥珀酰化（K251-Su）水平升高，且吸烟者的GAPDH K251-Su显著高于不吸烟者。肺癌细胞暴露于香烟烟雾提取物中导致谷氨酰胺摄取增加和GAPDH K251-Su增强。缺氧和营养缺乏微环境中癌细胞的谷氨酰胺摄取为K251位点的GAPDH琥珀酰化提供了琥珀酰辅酶A供体，这一过程由酰基转移酶p300催化。K251-Su通过抑制TRIM4介导的K254泛素化增加了GAPDH的稳定性。GAPDH K251-Su增强了糖酵解和谷氨酰胺还原羧化，以满足细胞生长需求并支持在缺氧和营养耗尽条件下的存活，促进肿瘤生长和转移。这些发现表明，吸烟通过GAPDH琥珀酰化介导癌细胞的代谢重编程，从而推动NSCLC进展。
吸烟诱导的GAPDH琥珀酰化协调糖酵解和谷氨酰胺代谢，并支持肺癌细胞在应激微环境中的存活以促进肿瘤进展，突出了戒烟作为针对癌症代谢的潜在策略。
