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Myostatin is a novel tumoral factor that induces cancer cachexia
Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of informati...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408049/ https://www.ncbi.nlm.nih.gov/pubmed/22621320 http://dx.doi.org/10.1042/BJ20112024 |
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author | Lokireddy, Sudarsanareddy Wijesoma, Isuru Wijerupage Bonala, Sabeera Wei, Meng Sze, Siu Kwan McFarlane, Craig Kambadur, Ravi Sharma, Mridula |
author_facet | Lokireddy, Sudarsanareddy Wijesoma, Isuru Wijerupage Bonala, Sabeera Wei, Meng Sze, Siu Kwan McFarlane, Craig Kambadur, Ravi Sharma, Mridula |
author_sort | Lokireddy, Sudarsanareddy |
collection | PubMed |
description | Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGFβ (transforming growth factor β) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin–proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-κB (nuclear factor κB) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/PI3K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy–lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice. |
format | Online Article Text |
id | pubmed-3408049 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-34080492012-08-06 Myostatin is a novel tumoral factor that induces cancer cachexia Lokireddy, Sudarsanareddy Wijesoma, Isuru Wijerupage Bonala, Sabeera Wei, Meng Sze, Siu Kwan McFarlane, Craig Kambadur, Ravi Sharma, Mridula Biochem J Research Article Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGFβ (transforming growth factor β) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin–proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-κB (nuclear factor κB) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/PI3K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy–lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice. Portland Press Ltd. 2012-07-27 2012-08-15 /pmc/articles/PMC3408049/ /pubmed/22621320 http://dx.doi.org/10.1042/BJ20112024 Text en © 2012 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by-nc/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Lokireddy, Sudarsanareddy Wijesoma, Isuru Wijerupage Bonala, Sabeera Wei, Meng Sze, Siu Kwan McFarlane, Craig Kambadur, Ravi Sharma, Mridula Myostatin is a novel tumoral factor that induces cancer cachexia |
title | Myostatin is a novel tumoral factor that induces cancer cachexia |
title_full | Myostatin is a novel tumoral factor that induces cancer cachexia |
title_fullStr | Myostatin is a novel tumoral factor that induces cancer cachexia |
title_full_unstemmed | Myostatin is a novel tumoral factor that induces cancer cachexia |
title_short | Myostatin is a novel tumoral factor that induces cancer cachexia |
title_sort | myostatin is a novel tumoral factor that induces cancer cachexia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408049/ https://www.ncbi.nlm.nih.gov/pubmed/22621320 http://dx.doi.org/10.1042/BJ20112024 |
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