IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling.
10.1097/CM9.0000000000002628
- VernacularTitle:IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling
- Author:
Xiaohui WANG
1
;
Jia LI
1
;
Wei ZHANG
1
;
Feng WANG
2
;
Yunzi WU
3
;
Yulin GUO
1
;
Dong WANG
4
;
Xinfeng YU
4
;
Ang LI
1
;
Fei LI
1
;
Yibin XIE
3
Author Information
1. Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
2. Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China.
3. Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
4. Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
- Publication Type:Journal Article
- MeSH:
Humans;
Insulin-Like Growth Factor Binding Protein 3/metabolism*;
Culture Media, Conditioned/pharmacology*;
Cachexia/pathology*;
Gastrointestinal Neoplasms;
Somatomedins/metabolism*;
Insulins/metabolism*;
Lipids
- From:
Chinese Medical Journal
2023;136(8):974-985
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia. In addition to systemic immune/inflammatory effects in response to tumor progression, tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss. However, the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood.
METHODS:The yki -gut tumors were induced in fruit flies. Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3 (IGFBP-3) treated cells. Immunoblotting was used to display phenotypes of tumor cells and adipocytes. Quantitative polymerase chain reaction (qPCR) analysis was carried out to examine the gene expression levels such as Acc1 , Acly , and Fasn et al .
RESULTS:In this study, it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes. IGFBP-3, which is highly expressed in cachectic tumor cells, antagonized insulin/IGF-like signaling (IIS) and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes. Conditioned medium from cachectic tumor cells, such as Capan-1 and C26 cells, contained excessive IGFBP-3 that potently induced lipolysis in adipocytes. Notably, neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes. Furthermore, cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS, ensuring their escape from IGFBP-3-associated growth suppression. Finally, cachectic tumor-derived ImpL2, the IGFBP-3 homolog, also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila . Most importantly, IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients, especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients.
CONCLUSION:Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.
