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IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling
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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2003
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278738/ https://www.ncbi.nlm.nih.gov/pubmed/37014770 http://dx.doi.org/10.1097/CM9.0000000000002628 |
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author | Wang, Xiaohui Li, Jia Zhang, Wei Wang, Feng Wu, Yunzi Guo, Yulin Wang, Dong Yu, Xinfeng Li, Ang Li, Fei Xie, Yibin |
author_facet | Wang, Xiaohui Li, Jia Zhang, Wei Wang, Feng Wu, Yunzi Guo, Yulin Wang, Dong Yu, Xinfeng Li, Ang Li, Fei Xie, Yibin |
author_sort | Wang, Xiaohui |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10278738 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2003 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-102787382023-06-20 IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling Wang, Xiaohui Li, Jia Zhang, Wei Wang, Feng Wu, Yunzi Guo, Yulin Wang, Dong Yu, Xinfeng Li, Ang Li, Fei Xie, Yibin Chin Med J (Engl) Original Article 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. Lippincott Williams & Wilkins 2003-04-04 2023-04-20 /pmc/articles/PMC10278738/ /pubmed/37014770 http://dx.doi.org/10.1097/CM9.0000000000002628 Text en Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
spellingShingle | Original Article Wang, Xiaohui Li, Jia Zhang, Wei Wang, Feng Wu, Yunzi Guo, Yulin Wang, Dong Yu, Xinfeng Li, Ang Li, Fei Xie, Yibin IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling |
title | IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling |
title_full | IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling |
title_fullStr | IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling |
title_full_unstemmed | IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling |
title_short | IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling |
title_sort | igfbp-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278738/ https://www.ncbi.nlm.nih.gov/pubmed/37014770 http://dx.doi.org/10.1097/CM9.0000000000002628 |
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