STAT3 promotes IFNγ/TNFα‐induced muscle wasting in an NF‐κB‐dependent and IL‐6‐independent manner
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 both in vitro and in vivo independently 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 the iNos gene 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.
Other Information
Published in: EMBO Molecular Medicine
License: http://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.15252/emmm.201607052
Funding
Qatar National Research Fund (NPRP8‐457‐3‐101), HuR-induced Cell Death of Breast Cancer Cells and Tumors: Molecular Mechanisms and Clinical Implication.
History
Language
- English
Publisher
Springer NaturePublication Year
- 2017
License statement
This Item is licensed under the Creative Commons Attribution 4.0 International License.Institution affiliated with
- Hamad Bin Khalifa University
- College of Science and Engineering - HBKU