p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice
| Autor: | Ka Wai Thomas Sin, Hui Ding, HoangAnh Amy Doan, Yiman Wang, Yahui Wei, Guohua Zhang, Yi-Ping Li, Zhelong Liu, Song Gao, Hongyu Miao |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Physiology lcsh:Medicine Protein degradation Biochemistry Genetics and Molecular Biology (miscellaneous) cachexia 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation medicine Myocyte lcsh:QH301-705.5 030304 developmental biology ULK1 0303 health sciences Chemistry lcsh:R Autophagy AMPK Skeletal muscle muscle wasting 3. Good health Cell biology medicine.anatomical_structure lcsh:Biology (General) 030220 oncology & carcinogenesis C/EBPβ Molecular Medicine Phosphorylation Gabarapl1 LC3b Research Article |
| Zdroj: | Cell Stress Cell Stress, Vol 2, Iss 11, Pp 311-324 (2018) |
| ISSN: | 2523-0204 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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