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

Abstract

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.

• Authors: Scott E Mulder, Aneesha Dasgupta, Ryan J King, Jaime Abrego, Kuldeep S Attri, Divya Murthy, Surendra K Shukla, Pankaj K Singh
• Journal: Cancer letters (Cancer Lett) Vol. 491 Pg. 70-77 (10 28 2020) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 32735910 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Anthracenes
• Muscle Proteins
• pyrazolanthrone
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Anthracenes (pharmacology, therapeutic use)
• Cachexia (drug therapy, etiology, metabolism)
• Cell Line, Tumor
• Female
• Humans
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, physiology)
• MAP Kinase Signaling System (physiology)
• Mice
• Muscle Fibers, Skeletal (pathology)
• Muscle Proteins (metabolism)
• Muscle, Skeletal (metabolism)
• Pancreatic Neoplasms (complications, drug therapy, metabolism)