title: STAT3 promotes IFNγ/TNFα-induced muscle wasting in an NF-κB-dependent and IL-6-independent manner.
abstract: Cachexia is a debilitating syndrome characterized by involuntary muscle wasting that is triggered at the late stage of many cancers. While the multifactorial nature of this syndrome and the implication of cytokines such as IL-6, IFNγ, and TNFα is well established, we still do not know how various effector pathways collaborate together to trigger muscle atrophy. Here, we show that IFNγ/TNFα promotes the phosphorylation of STAT3 on Y705 residue in the cytoplasm of muscle fibers by activating JAK kinases. Unexpectedly, this effect occurs bothin vitroandin vivoindependently of IL-6, which is considered as one of the main triggers of STAT3-mediated muscle wasting. pY-STAT3 forms a complex with NF-κB that is rapidly imported to the nucleus where it is recruited to the promoter of theiNosgene to activate the iNOS/NO pathway, a well-known downstream effector of IFNγ/TNFα-induced muscle loss. Together, these findings show that STAT3 and NF-κB respond to the same upstream signal and cooperate to promote the expression of pro-cachectic genes, the identification of which could provide effective targets to combat this deadly syndrome.
authors.affiliation: Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC, Canada.
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Ma
authors.affiliation: Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC, Canada.
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Sanchez
authors.affiliation: Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC, Canada.
authors.forename: Derek T
authors.initials: DT
authors.lastname: Hall
authors.affiliation: Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC, Canada.
authors.forename: Anne-Marie K
authors.initials: AK
authors.lastname: Tremblay
authors.affiliation: Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC, Canada.
authors.forename: Sergio
authors.initials: S
authors.lastname: Di Marco
authors.affiliation: Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC, Canada imed.gallouzi@mcgill.ca igallouzi@hbku.edu.qa.|Life Sciences Division, College of Science and Engineering, Hamad Bin Khalifa University (HBKU), Education City, Doha, Qatar.
authors.forename: Imed-Eddine
authors.identifier: 0000-0003-4758-4835
authors.initials: IE
authors.lastname: Gallouzi
mesh_terms: D000818:Animals; D002460:Cell Line; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009132:Muscles / Q000276:immunology / Q000473:pathology; D009133:Muscular Atrophy / Q000276:immunology* / Q000473:pathology; D016328:NF-kappa B / Q000276:immunology*; D060066:Protein Interaction Maps; D050796:STAT3 Transcription Factor / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D019282:Wasting Syndrome / Q000276:immunology* / Q000473:pathology
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: 
  iNOS
  ; NF‐κB; STAT3; inflammation; muscle wasting