首页|GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia

GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia

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Cachexia,which affects 50-80％of cancer patients,is a debilitating syndrome that leads to 20％of cancer-related deaths.A key feature of cachexia is adipose tissue atrophy,but how it contributes to the development of cachexia is poorly understood.Here,we demonstrate in mouse models of cancer cachexia that white adipose tissue browning,which can be a characteristic early-onset manifestation,occurs prior to the loss of body weight and skeletal muscle wasting.By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours,we identified a molecular chaperone,Glucose-regulated protein 75(GRP75),as a critical mediator of adipocyte browning.Mechanistically,GRP75 binds adenine nucleotide translocase 2(ANT2)to form a GRP75-ANT2 complex.Strikingly,stabilized ANT2 enhances its interaction with uncoupling protein 1,leading to elevated expression of the latter,which,in turn,promotes adipocyte browning.Treatment with withanone,a GRP75 inhibitor,can reverse this browning and alleviate cachectic phenotypes in vivo.Overall,our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.

Xu Chen、Qingnan Wu、Wei Gong、Shaolong Ju、Jiawen Fan、Xiaohan Gao、Xingyang Liu、Xiao Lei、Siqi Liu、Xiangdong Ming、Qianyu Wang、Ming Fu、Yongmei Song、Yan Wang、Qimin Zhan

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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,100021 Beijing,China

Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Laboratory of Molecular Oncology,Peking University Cancer Hospital & Institute,100142 Beijing,China

Peking University-Yunnan Baiyao International Medical Research Center,100191 Beijing,China

Center for Infection and Immunity,The Fifth Affiliated Hospital of Sun Yat-sen University,Zhuhai,China

Department of Biochemistry and Biophysics,School of Basic Medical Sciences,Peking University Health Science Center,Beijing,China

Research Unit of Molecular Cancer Research,Chinese Academy of Medical Sciences,Beijing,China

Soochow Uni

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National Key Research and Development Program of China 1 under Y.WNational Natural Science Foundation of China 2 under Q.ZNational Natural Science Foundation of China 2 under Q.ZNational Natural Science Foundation of China 3 under Y.WResearch Unit of Molecular Cancer Research,Chinese Academy of Medical Sciences,CAMS Innovation Fund for Medical Sciences 4 uScience Foundation of Peking University Cancer Hospital 5 under Q.Z

number 2022YFC3400904number 8198810181830086number 82173152number 2019-I2M-5-081number 17-01

2024

10.1038/s41392-024-01950-w

信号转导与靶向治疗(英文)

信号转导与靶向治疗(英文)

CSTPCD
ISSN：
年,卷(期)：2024.9(10)