恶性肿瘤
生物
癌症研究
糖酵解
DNA
基底细胞
癌
细胞
病理
化学
医学
内科学
新陈代谢
生物化学
作者
Hui Yun Wang,Yanyang Zhang,Yu Tian,Wanlin Yang,Yan Wang,H. C. Hou,Hanbo Pan,Siyu Pei,Hongda Zhu,Zenan Gu,Yanyun Zhang,Dongfang Dai,Wei Chen,Mingyue Zheng,Qingquan Luo,Yichuan Xiao,Jia Huang
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-01-10
卷期号:84 (5): 688-702
标识
DOI:10.1158/0008-5472.can-23-0744
摘要
Abstract 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.
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