p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice
Authors:Zhelong Liu1, 2,†, Ka Wai Thomas Sin1,†, Hui Ding1,3, HoangAnh Amy Doan1, Song Gao1, Hongyu Miao4, Yahui Wei1,#, Yiman Wang1,#, Guohua Zhang1, and Yi-Ping Li1
1 Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, Texas 77030, USA.
2 Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3 Department of Respiratory Medicine, Yixing Hospital affiliated to Jiangsu University, Yixing, China.
4 School of Public Health, University of Texas Health Science Center, Houston, Texas 77030, USA.
† These authors contributed equally.
# Yahui Wei and Yiman Wang were medical students of Jiaotong University, Shanghai, China participating in the Summer Research Program at McGovern Medical School, University of Texas Health Science Center at Houston.
Keywords:
cachexia, muscle wasting, C/EBPβ, LC3b, Gabarapl1, ULK1.
Abbreviations:
AMPK – AMP-activated Protein Kinase,
C/EBPβ – CCAAT/enhancer-binding protein beta,
GFP – Green fluorescence protein,
HSP – Heat Shock Protein,
IL-6 – Interleukin 6
LCM – LLC Conditioned Medium,
LLC – Lewis Lung Carcinoma,
MAPK – Mitogen-Activated Protein Kinase,
MKO – Muscle specific Knock Out,
TA – Tibialis Anterior,
TLR4 – Toll-Like Receptor 4,
ULK1 – Unc-51 Like autophagy activating Kinase 1,
UPP – Ubiquitin-Proteasome Pathway.
Corresponding Author(s):
Conflict of interest statement:
The authors declare that they have no conflict of interest.
Please cite this article as:
Zhelong Liu, Ka Wai Thomas Sin, Hui Ding, HoangAnh Amy Doan, Song Gao, Hongyu Miao, Yahui Wei, Yiman Wang, Guohua Zhang, and Yi-Ping Li (2018). p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice. Cell Stress 2(11): 311-324. doi: 10.15698/cst2018.11.163
© 2018 Liu et al. 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.
Abstract:
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 p38β 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.