Abstract

Cancer cachexia is a metabolic disorder characterized by skeletal muscle wasting and white adipose tissue browning. Specific functions of several hormones, growth factors, and cytokines derived from tumors can trigger cachexia. Moreover, adipose tissue lipolysis might explain weight loss that occurs owing to cachexia. Extracellular vesicles (EVs) are involved in intercellular communication. However, whether EVs participate in lipolysis induced by cancer cachexia has not been thoroughly investigated. Using Lewis lung carcinoma (LLC) cell culture, we tested whether LLC cell-derived EVs can induce lipolysis in 3T3-L1 adipocytes. EVs derived from LLC cells were isolated and characterized biochemically and biophysically. Western blotting and glycerol assay were used to study lipolysis. LLC cell-derived EVs induced lipolysis in vivo and vitro. EVs fused directly with target 3T3-L1 adipocytes and transferred parathyroid hormone-related protein (PTHrP), activating the PKA signaling pathway in 3T3-L1 adipocytes. Blocking PTHrP activity in LLC-EVs using a neutralizing antibody and by knocking down PTHR expression prevented lipolysis in adipocytes. Inhibiting the PKA signaling pathway also prevents the lipolytic effects of EVs. In vivo, suppression of LLC-EVs release by knocking down Rab27A alleviated white adipose tissue browning and lipolysis. Our data showed that LLC cell-derived EVs induced adipocyte lipolysis via the extracellular PTHrP-mediated PKA pathway. Our data demonstrate that LLC-EVs induce lipolysis in vitro and vivo by delivering PTHrP, which interacts with PTHR. The lipolytic effect of LLC-EVs was abrogated by PTHR knockdown and treatment with a neutralizing anti-PTHrP antibody. Together, these data show that LLC-EV-induced lipolysis is mediated by extracellular PTHrP. These findings suggest a novel mechanism of lipid droplet loss and identify a potential therapeutic strategy for cancer cachexia.

Details

Title
Extracellular vesicles-released parathyroid hormone-related protein from Lewis lung carcinoma induces lipolysis and adipose tissue browning in cancer cachexia
Author
Hu, Wenjun 1 ; Xiong Hairong 1 ; Ru Zeyuan 1 ; Zhao, Yan 1 ; Zhou, Yali 1 ; Xie Kairu 1 ; Xiao, Wen 2 ; Xiong Zhiyong 2 ; Wang, Cheng 2 ; Yuan Changfei 2 ; Shi, Jian 2 ; Du Quansheng 3 ; Zhang, Xiaoping 2 ; Yang, Hongmei 1   VIAFID ORCID Logo 

1  Huazhong University of Science and Technology, Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Wuhan, China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223) 
2  Huazhong University of Science and Technology, Department of Urology, Union Hospital, Tongji Medical College, Wuhan, China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223) 
3  Augusta University, Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta, USA (GRID:grid.410427.4) (ISNI:0000 0001 2284 9329) 
Publication year
2021
Publication date
Jan 2021
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41419-020-03382-0
ProQuest document ID
2482357811
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.