2. Academic Validation
  3. GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia

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

  • Signal Transduct Target Ther. 2024 Sep 26;9(1):253. doi: 10.1038/s41392-024-01950-w.
Xu Chen 1,  Qingnan Wu 2,  Wei Gong 3,  Shaolong Ju 4,  Jiawen Fan 2,  Xiaohan Gao 1,  Xingyang Liu 2,  Xiao Lei 5,  Siqi Liu 2,  Xiangdong Ming 5,  Qianyu Wang 2,  Ming Fu 1,  Yongmei Song 1,  Yan Wang 6,  Qimin Zhan 7 8 9 10
Affiliations

Affiliations

  • 1 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.
  • 2 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China.
  • 3 Peking University-Yunnan Baiyao International Medical Research Center, 100191, Beijing, China.
  • 4 Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.
  • 5 Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 6 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China. wy305@126.com.
  • 7 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. zhanqimin@bjmu.edu.cn.
  • 8 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China. zhanqimin@bjmu.edu.cn.
  • 9 Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China. zhanqimin@bjmu.edu.cn.
  • 10 Soochow University Cancer Institute, Suzhou, 215000, China. zhanqimin@bjmu.edu.cn.
PMID: 39327432 DOI: 10.1038/s41392-024-01950-w
Abstract

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.

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