Increased Drp1 promotes autophagy and ESCC progression by mtDNA stress mediated cGAS-STING pathway

Journal of Experimental & Clinical Cancer Research

Hushan Yang¹  Junqi Liu²  Yuanyuan Wu³  Menglan Niu³  Yating Yang³  Hongliang Liu³  Jing Zhao³  Jiaxin Wang³  Hui Chen³  Shaogui Wan⁴  Dengke Bao⁵  Qi Yang⁶  Yujia Li⁶  Lixin Wan⁷  Yanming Wang⁸ 

[1] Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 19107, Philadelphia, PA, USA;Department of Radiation Oncology, the First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China;Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, 475004, Kaifeng, Henan, China;Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, 475004, Kaifeng, Henan, China;Center for Molecular Pathology, First Affiliated Hospital, Gannan Medical University, 341000, Ganzhou, Jiangxi, China;Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, 475004, Kaifeng, Henan, China;Nanyang Central Hospital, Henan University, 473000, Nanyang, Henan, China;Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, 475004, Kaifeng, Henan, China;School of Life Sciences, Henan University, 475004, Kaifeng, Henan, China;Nanyang Central Hospital, Henan University, 473000, Nanyang, Henan, China;School of Life Sciences, Henan University, 475004, Kaifeng, Henan, China;

关键词: Mitochondrial DNA stress;    Autophagy;    cGAS-STING signaling pathway;    Drp1;    Esophageal Squamous Cell Carcinoma;   

DOI  :  10.1186/s13046-022-02262-z

来源: Springer

【 摘 要 】

BackgroundMitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp1 is frequently upregulated in many cancers and is closely implicated in tumorigenesis. However, the mechanism underling Drp1 to influence tumor progression is largely unknown, especially in esophageal squamous cell carcinoma (ESCC).MethodsImmunohistochemistry was used to examine Drp1 and LC3B expression in tissues of ESCC patients. Autophagic vesicles were investigated by transmission electron microscopy. Fluorescent LC3B puncta and mitochondrial nucleoid were observed by fluorescent and confocal microscopy. Mitochondrial function was evaluated by mitochondrial membrane potential, ROS and ATP levels. Xenograft tumor model was performed in BALB/c nude mice to analyze the role of Drp1 on ESCC progression.ResultsWe found that Drp1 high expression is correlated with poor overall survival of ESCC patients. Drp1 overexpression promotes cell proliferation and xenograft ESCC tumor growth by triggering autophagy. Furthermore, we demonstrated that Drp1 overexpression disturbs mitochondrial function and subsequent induces mitochondrial DNA (mtDNA) released into the cytosol thereby inducing cytosolic mtDNA stress. Mechanistically, cytosolic mtDNA activates the cGAS-STING pathway and facilitates autophagy, which promotes ESCC cancer growth. Moreover, mtDNA digestion with DNase I and autophagy inhibition with chloroquine attenuates the cGAS-STING pathway activation and ESCC cancer growth.ConclusionsOur finding reveals that Drp1 overexpression induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the cGAS-STING pathway, triggers autophagy and promotes ESCC progression.

【 授权许可】

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