GRP75 触发白色脂肪组织褐变,促进癌症相关恶病质的形成

IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Signal Transduction and Targeted Therapy Pub Date : 2024-09-26 DOI:10.1038/s41392-024-01950-w
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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引用次数: 0

摘要

恶病质影响到 50-80% 的癌症患者,是一种使人衰弱的综合征,导致 20% 的癌症相关死亡。恶病质的一个主要特征是脂肪组织萎缩,但人们对脂肪组织如何导致恶病质的发生还知之甚少。在这里,我们在癌症恶病质小鼠模型中证明,白色脂肪组织褐变是一种早期发病的特征性表现,发生在体重减轻和骨骼肌萎缩之前。通过分析来自恶病质诱导肿瘤的细胞外囊泡中不同表达的蛋白质,我们发现了一种分子伴侣--葡萄糖调节蛋白 75(GRP75)--是脂肪细胞褐变的关键介质。从机理上讲,GRP75与腺嘌呤核苷酸转运酶2(ANT2)结合,形成GRP75-ANT2复合物。令人吃惊的是,稳定的 ANT2 会增强与解偶联蛋白 1 的相互作用,导致后者的表达升高,进而促进脂肪细胞褐变。用GRP75抑制剂--卡尼酮(withanone)治疗可逆转这种褐变,并减轻体内的糜烂表型。总之,我们的研究结果揭示了肿瘤衍生的 GRP75 在恶病质发展过程中调节白脂肪组织褐变的新机制,并提出了一种潜在的以白脂肪组织为中心的早期恶病质干预靶向方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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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来源期刊
Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
44.50
自引率
1.50%
发文量
384
审稿时长
5 weeks
期刊介绍: Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
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