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DNA-PK-Mediated Cytoplasmic DNA Sensing Stimulates Glycolysis to Promote Lung Squamous Cell Carcinoma Malignancy and Chemoresistance

文献类型：期刊论文

作者Wang, Hui6; Zhang, Yanyang6; Tian, Yu6; Yang, Wanlin6; Wang, Yan5; Hou, Hui4; Pan, Hanbo6; Pei, Siyu6; Zhu, Hongda6; Gu, Zenan6
刊名CANCER RESEARCH
出版日期2024-03-04
卷号84期号:5页码:688-702
ISSN号0008-5472
DOI10.1158/0008-5472.CAN-23-0744
通讯作者Huang, Jia(hayychw@njmu.edu.cn)
英文摘要DNA-PK is a cytoplasmic DNA sensor that activates ZAK/AKT/mTOR signaling and boosts glycolysis to enhance malignancy and chemoresistance of lung squamous cell carcinoma. Detection of cytoplasmic DNA is an essential biological mechanism that elicits IFN-dependent and immune-related responses. A better understanding of the mechanisms regulating cytoplasmic DNA sensing in tumor cells could help identify immunotherapeutic strategies to improve cancer treatment. Here we identified abundant cytoplasmic DNA accumulated in lung squamous cell carcinoma (LUSC) cells. DNA-PK, but not cGAS, functioned as a specific cytoplasmic DNA sensor to activate downstream ZAK/AKT/mTOR signaling, thereby enhancing the viability, motility, and chemoresistance of LUSC cells. DNA-PK-mediated cytoplasmic DNA sensing boosted glycolysis in LUSC cells, and blocking glycolysis abolished the tumor-promoting activity of cytoplasmic DNA. Elevated DNA-PK-mediated cytoplasmic DNA sensing was positively correlated with poor prognosis of human patients with LUSC. Targeting signaling activated by cytoplasmic DNA sensing with the ZAK inhibitor iZAK2 alone or in combination with STING agonist or anti-PD-1 antibody suppressed the tumor growth and improved the survival of mouse lung cancer models and human LUSC patient-derived xenografts model. Overall, these findings established DNA-PK-mediated cytoplasmic DNA sensing as a mechanism that supports LUSC malignancy and highlight the potential of targeting this pathway for treating LUSC.Significance: DNA-PK is a cytoplasmic DNA sensor that activates ZAK/AKT/mTOR signaling and boosts glycolysis to enhance malignancy and chemoresistance of lung squamous cell carcinoma.
WOS关键词CHROMOSOMAL INSTABILITY ; STING PATHWAY ; CANCER ; SENSOR ; INFLAMMATION ; ACTIVATION ; SENESCENCE ; PROTEIN ; BREAKS
资助项目National Natural Science Foundation of China[81972176] ; National Natural Science Foundation of China[82201921] ; National Natural Science Foundation of China[82030041] ; National Key R&D Program of China[2018YFA0902703] ; National Key R&D Program of China[2018YFA0107201] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB39030300] ; CAS Project for Young Scientist in Basic Research[YSBR-076] ; Shanghai Municipal Science and Technology[20XD1424600] ; Shanghai Municipal Science and Technology[21140905000] ; China Postdoctoral Science Foundation[2021M702163] ; Science and Technology Development Foundation of Shanghai Chest Hospital[2021YNJCM10]
WOS研究方向Oncology
语种英语
WOS记录号WOS:001179389600005
出版者AMER ASSOC CANCER RESEARCH
源URL[http://119.78.100.183/handle/2S10ELR8/310363]  
专题新药研究国家重点实验室
通讯作者Huang, Jia
作者单位1.Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Sch Med, Shanghai 200030, Peoples R China
2.Nanjing Med Univ, Dept Resp & Crit Care Med, Affiliated Huaia Peoples Hosp 1, Huaian, Jiangsu, Peoples R China
3.Nanjing Med Univ, Affiliated Canc Hosp, Jiangsu Inst Canc Res, Jiangsu Canc Hosp, Nanjing, Jiangsu, Peoples R China
4.Univ Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med,Chinese Acad Sci, Shanghai, Peoples R China
5.Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Chinese Acad Sci, Key Lab Tissue Microenvironm & Tumor, Shanghai, Peoples R China
6.Shanghai Jiao Tong Univ, Sch Med, Shanghai Chest Hosp, Shanghai Lung Canc Ctr,Dept Thorac Surg Oncol, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Hui,Zhang, Yanyang,Tian, Yu,et al. DNA-PK-Mediated Cytoplasmic DNA Sensing Stimulates Glycolysis to Promote Lung Squamous Cell Carcinoma Malignancy and Chemoresistance[J]. CANCER RESEARCH,2024,84(5):688-702.
APA Wang, Hui.,Zhang, Yanyang.,Tian, Yu.,Yang, Wanlin.,Wang, Yan.,...&Huang, Jia.(2024).DNA-PK-Mediated Cytoplasmic DNA Sensing Stimulates Glycolysis to Promote Lung Squamous Cell Carcinoma Malignancy and Chemoresistance.CANCER RESEARCH,84(5),688-702.
MLA Wang, Hui,et al."DNA-PK-Mediated Cytoplasmic DNA Sensing Stimulates Glycolysis to Promote Lung Squamous Cell Carcinoma Malignancy and Chemoresistance".CANCER RESEARCH 84.5(2024):688-702.

入库方式： OAI收割

来源：上海药物研究所

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