JNK signaling contributes to skeletal muscle wasting and protein turnover in pancreatic cancer cachexia.

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Tytuł:: JNK signaling contributes to skeletal muscle wasting and protein turnover in pancreatic cancer cachexia.
Autorzy:: Mulder SE; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Dasgupta A; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
King RJ; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Abrego J; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Attri KS; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Murthy D; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Shukla SK; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address: .
Singh PK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address: .
Źródło:: Cancer letters [Cancer Lett] 2020 Oct 28; Vol. 491, pp. 70-77. Date of Electronic Publication: 2020 Jul 28.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural
Język:: English
Imprint Name(s):: Publication: Limerick : Elsevier Science Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.
MeSH Terms:: Cachexia/*etiology
JNK Mitogen-Activated Protein Kinases/*physiology
MAP Kinase Signaling System/*physiology
Muscle Proteins/*metabolism
Muscle, Skeletal/*metabolism
Pancreatic Neoplasms/*complications
Animals ; Anthracenes/pharmacology ; Anthracenes/therapeutic use ; Cachexia/drug therapy ; Cachexia/metabolism ; Cell Line, Tumor ; Female ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors ; Mice ; Muscle Fibers, Skeletal/pathology ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/metabolism
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Grant Information:: P30 CA036727 United States CA NCI NIH HHS; R01 CA210439 United States CA NCI NIH HHS; T32 CA009476 United States CA NCI NIH HHS
Contributed Indexing:: Keywords: Cancer cachexia; JNK signaling; Muscle wasting; Pancreatic cancer; Ubiquitin ligases
Substance Nomenclature:: 0 (Anthracenes)
0 (Muscle Proteins)
1TW30Y2766 (pyrazolanthrone)
EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
Entry Date(s):: Date Created: 20200801 Date Completed: 20210222 Latest Revision: 20211029
Update Code:: 20240104
PubMed Central ID:: PMC7541723
DOI:: 10.1016/j.canlet.2020.07.025
PMID:: 32735910
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Cancer cachexia patients experience significant muscle wasting, which impairs the quality of life and treatment efficacy for patients. Skeletal muscle protein turnover is imparted by increased expression of ubiquitin-proteasome pathway components. Mitogen-activated protein kinases p38 and ERK have been shown to augment E3 ubiquitin ligase expression. Utilizing reverse-phase protein arrays, we identified pancreatic cancer cell-conditioned media-induced activation of JNK signaling in myotubes differentiated from C2C12 myoblasts. Inhibition of JNK signaling with SP600125 reduced cancer cell-conditioned media-induced myotube atrophy, myosin heavy chain protein turnover, and mRNA expression of cachexia-specific ubiquitin ligases Trim63 and Fbxo32. Furthermore, utilizing an orthotopic pancreatic cancer cachexia mouse model, we demonstrated that treatment of tumor-bearing mice with SP600125 improved longitudinal measurements of forelimb grip strength. Post-necropsy measurements demonstrated that SP600125 treatment rescued body weight, carcass weight, and gastrocnemius muscle weight loss without impacting tumor growth. JNK inhibitor treatment also rescued myofiber degeneration and reduced the muscle expression of Trim63 and Fbxo32. These data demonstrate that JNK signaling contributes to muscle wasting in cancer cachexia, and its inhibition has the potential to be utilized as an anti-cachectic therapy.
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