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

Author:

Wang Hui1ORCID,Zhang Yanyang1ORCID,Tian Yu1ORCID,Yang Wanlin1ORCID,Wang Yan2ORCID,Hou Hui3ORCID,Pan Hanbo1ORCID,Pei Siyu1ORCID,Zhu Hongda1ORCID,Gu Zenan1ORCID,Zhang Yanyun2ORCID,Dai Dongfang4ORCID,Chen Wei5ORCID,Zheng Mingyue3ORCID,Luo Qingquan1ORCID,Xiao Yichuan2ORCID,Huang Jia1ORCID

Affiliation:

1. 1Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.

2. 2Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, P.R. China.

3. 3Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, P.R. China.

4. 4The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, P.R. China.

5. 5Department of Respiratory and Critical Care Medicine, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, P.R. China.

Abstract

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.

Funder

National Natural Science Foundation of China

National Key Research and Development Program of China

Strategic Priority Research Program of the Chinese Academy of Sciences

CAS Project for Young Scientist in Basic Research

Shanghai Municipal Science and Technology

Publisher

American Association for Cancer Research (AACR)

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