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p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice

Muscle wasting is the key manifestation of cancer-associated cachexia, a lethal metabolic disorder seen in over 50% of cancer patients. Autophagy is activated in cachectic muscle of cancer hosts along with the ubiquitin-proteasome pathway (UPP), contributing to accelerated protein degradation and mu...

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Autores principales: Liu, Zhelong, Sin, Ka Wai Thomas, Ding, Hui, Doan, HoangAnh Amy, Gao, Song, Miao, Hongyu, Wei, Yahui, Wang, Yiman, Zhang, Guohua, Li, Yi-Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Shared Science Publishers OG 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551802/
https://www.ncbi.nlm.nih.gov/pubmed/31225455
http://dx.doi.org/10.15698/cst2018.11.163
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author Liu, Zhelong
Sin, Ka Wai Thomas
Ding, Hui
Doan, HoangAnh Amy
Gao, Song
Miao, Hongyu
Wei, Yahui
Wang, Yiman
Zhang, Guohua
Li, Yi-Ping
author_facet Liu, Zhelong
Sin, Ka Wai Thomas
Ding, Hui
Doan, HoangAnh Amy
Gao, Song
Miao, Hongyu
Wei, Yahui
Wang, Yiman
Zhang, Guohua
Li, Yi-Ping
author_sort Liu, Zhelong
collection PubMed
description Muscle wasting is the key manifestation of cancer-associated cachexia, a lethal metabolic disorder seen in over 50% of cancer patients. Autophagy is activated in cachectic muscle of cancer hosts along with the ubiquitin-proteasome pathway (UPP), contributing to accelerated protein degradation and muscle wasting. However, established signaling mechanism that activates autophagy in response to fasting or denervation does not seem to mediate cancer-provoked autophagy in skeletal myocytes. Here, we show that p38β MAPK mediates autophagy activation in cachectic muscle of tumor-bearing mice via novel mechanisms. Complementary genetic and pharmacological manipulations reveal that activation of p38β MAPK, but not p38α MAPK, is necessary and sufficient for Lewis lung carcinoma (LLC)-induced autophagy activation in skeletal muscle cells. Particularly, muscle-specific knockout of p38β MAPK abrogates LLC tumor-induced activation of autophagy and UPP, sparing tumor-bearing mice from muscle wasting. Mechanistically, p38β MAPK-mediated activation of transcription factor C/EBPβ is required for LLC-induced autophagy activation, and upregulation of autophagy-related genes LC3b and Gabarapl1. Surprisingly, ULK1 activation (phosphorylation at S555) by cancer requires p38β MAPK, rather than AMPK. Activated ULK1 forms a complex with p38β MAPK in myocytes, which is markedly increased by a tumor burden. Overexpression of a constitutively active p38Tbeta; MAPK in HEK293 cells increases phosphorylation at S555 and other amino acid residues of ULK1, but not several of AMPK-mediated sites. Finally, ULK1 activation is abrogated in tumor-bearing mice with muscle-specific knockout of p38β MAPK. Thus, p38β MAPK appears a key mediator of cancer-provoked autophagy activation, and a therapeutic target of cancer-induced muscle wasting.
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spelling pubmed-65518022019-06-20 p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice Liu, Zhelong Sin, Ka Wai Thomas Ding, Hui Doan, HoangAnh Amy Gao, Song Miao, Hongyu Wei, Yahui Wang, Yiman Zhang, Guohua Li, Yi-Ping Cell Stress Research Article Muscle wasting is the key manifestation of cancer-associated cachexia, a lethal metabolic disorder seen in over 50% of cancer patients. Autophagy is activated in cachectic muscle of cancer hosts along with the ubiquitin-proteasome pathway (UPP), contributing to accelerated protein degradation and muscle wasting. However, established signaling mechanism that activates autophagy in response to fasting or denervation does not seem to mediate cancer-provoked autophagy in skeletal myocytes. Here, we show that p38β MAPK mediates autophagy activation in cachectic muscle of tumor-bearing mice via novel mechanisms. Complementary genetic and pharmacological manipulations reveal that activation of p38β MAPK, but not p38α MAPK, is necessary and sufficient for Lewis lung carcinoma (LLC)-induced autophagy activation in skeletal muscle cells. Particularly, muscle-specific knockout of p38β MAPK abrogates LLC tumor-induced activation of autophagy and UPP, sparing tumor-bearing mice from muscle wasting. Mechanistically, p38β MAPK-mediated activation of transcription factor C/EBPβ is required for LLC-induced autophagy activation, and upregulation of autophagy-related genes LC3b and Gabarapl1. Surprisingly, ULK1 activation (phosphorylation at S555) by cancer requires p38β MAPK, rather than AMPK. Activated ULK1 forms a complex with p38β MAPK in myocytes, which is markedly increased by a tumor burden. Overexpression of a constitutively active p38Tbeta; MAPK in HEK293 cells increases phosphorylation at S555 and other amino acid residues of ULK1, but not several of AMPK-mediated sites. Finally, ULK1 activation is abrogated in tumor-bearing mice with muscle-specific knockout of p38β MAPK. Thus, p38β MAPK appears a key mediator of cancer-provoked autophagy activation, and a therapeutic target of cancer-induced muscle wasting. Shared Science Publishers OG 2018-10-10 /pmc/articles/PMC6551802/ /pubmed/31225455 http://dx.doi.org/10.15698/cst2018.11.163 Text en Copyright: © 2018 Liu et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
spellingShingle Research Article
Liu, Zhelong
Sin, Ka Wai Thomas
Ding, Hui
Doan, HoangAnh Amy
Gao, Song
Miao, Hongyu
Wei, Yahui
Wang, Yiman
Zhang, Guohua
Li, Yi-Ping
p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice
title p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice
title_full p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice
title_fullStr p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice
title_full_unstemmed p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice
title_short p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice
title_sort p38β mapk mediates ulk1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551802/
https://www.ncbi.nlm.nih.gov/pubmed/31225455
http://dx.doi.org/10.15698/cst2018.11.163
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