Extracellular vesicles derived from oesophageal cancer containing P4HB promote muscle wasting via regulating PHGDH/Bcl‐2/caspase‐3 pathway

Journal of Extracellular Vesicles

Fang Lu¹  Jie Chen²  Weimin Zhang²  Yiren Cao²  Yan Wang²  Di Yang²  Liying Ma³  Guangchao Wang³  Xiaohan Gao³  Ming Fu³  Leilei Zheng³  Yongmei Song³  Xu Chen³  Qimin Zhan³ 

[1] Department of Ophthalmology West China Hospital Sichuan University Chengdu China;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Beijing China;State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China;

关键词: apoptosis;    cachexia;    oesophageal cancer;    extracellular vesicles;    inhibitor;    muscle wasting;   

DOI  :  10.1002/jev2.12060

来源: DOAJ

【 摘 要 】

Abstract Cachexia, characterized by loss of skeletal muscle mass and function, is estimated to inflict the majority of patients with oesophageal squamous cell carcinoma (ESCC) and associated with their poor prognosis. However, its underlying mechanisms remain elusive. Here, we developed an ESCC‐induced cachexia mouse model using human xenograft ESCC cell lines and found that ESCC‐derived extracellular vesicles (EVs) containing prolyl 4‐hydroxylase subunit beta (P4HB) induced apoptosis of skeletal muscle cells. We further identified that P4HB promoted apoptotic response through activating ubiquitin‐dependent proteolytic pathway and regulated the stability of phosphoglycerate dehydrogenase (PHGDH) and subsequent antiapoptotic protein Bcl‐2. Additionally, we proved that the P4HB inhibitor, CCF642, not only rescued apoptosis of muscle cells in vitro, but also prevented body weight loss and muscle wasting in ESCC‐induced cachexia mouse model. Overall, these findings demonstrate a novel pathway for ESCC‐induced muscle wasting and advocate for the development of P4HB as a potential intervention target for cachexia in patients with ESCC.

【 授权许可】

Unknown