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Increased eEF2K Promotes Glycolysis and Aggressive Behaviors of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

OBJECTIVE: Aggressive phenotype and abnormal glycolytic metabolism of fibroblast-like synoviocytes (FLSs) are essential to joint inflammation and damage in rheumatoid arthritis (RA). Eukaryotic elongation factor-2 kinase (eEF2K) is a negative regulator of protein synthesis and has been shown to play...

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Autores principales: Chen, Dongying, Cai, Xiaoyan, Ouyang, Hui, Yuan, Shiwen, Wang, Xiaodong, Lin, Lian, Chen, Zhiqing, Huang, Mingcheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8922331/
https://www.ncbi.nlm.nih.gov/pubmed/35300214
http://dx.doi.org/10.2147/JIR.S337620
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author Chen, Dongying
Cai, Xiaoyan
Ouyang, Hui
Yuan, Shiwen
Wang, Xiaodong
Lin, Lian
Chen, Zhiqing
Huang, Mingcheng
author_facet Chen, Dongying
Cai, Xiaoyan
Ouyang, Hui
Yuan, Shiwen
Wang, Xiaodong
Lin, Lian
Chen, Zhiqing
Huang, Mingcheng
author_sort Chen, Dongying
collection PubMed
description OBJECTIVE: Aggressive phenotype and abnormal glycolytic metabolism of fibroblast-like synoviocytes (FLSs) are essential to joint inflammation and damage in rheumatoid arthritis (RA). Eukaryotic elongation factor-2 kinase (eEF2K) is a negative regulator of protein synthesis and has been shown to play an important role in regulating various cellular processes and promoting glycolysis in tumor cells. However, the role of eEF2K in regulating the pathogenic FLS behaviors is unknown. METHODS: A specific inhibitor of eEF2K, NH125, and siRNA were used to evaluate the role of eEF2K on RA FLSs in vitro. Collagen-induced arthritis (CIA) mice were used to evaluate the in vivo effect of eEF2K. Cell migration, invasion of RA FLSs were assessed by transwell or wound healing assays. Relative changes of cytokines were analyzed by quantitative real-time PCR, western blot and ELISA. RESULTS: Herein, we found an increased expression of eEF2K in synovial tissues and FLSs of RA patients. eEF2K knockdown by siRNA or treatment with NH125, an inhibitor of eEF2K, significantly reduced inflammation, migration/invasion, glucose uptake and lactate productions. eEF2K knockdown suppressed TNF-α-induced activation of NF-κB and AKT pathways in RA FLSs. Lactate reversed the inhibitory effect of eEF2K knockdown on inflammation and migration of RA FLSs. Moreover, lactate was also involved in eEF2K-mediated activation of NF-κB and AKT. NH125 treatment attenuated the severity of arthritis in collagen-induced arthritis mice. CONCLUSION: eEF2K inhibition suppressed glycolysis and aggressive behaviors of RA FLS, which indicated that targeting eEF2K may be a new strategy for the treatment of RA.
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spelling pubmed-89223312022-03-16 Increased eEF2K Promotes Glycolysis and Aggressive Behaviors of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis Chen, Dongying Cai, Xiaoyan Ouyang, Hui Yuan, Shiwen Wang, Xiaodong Lin, Lian Chen, Zhiqing Huang, Mingcheng J Inflamm Res Original Research OBJECTIVE: Aggressive phenotype and abnormal glycolytic metabolism of fibroblast-like synoviocytes (FLSs) are essential to joint inflammation and damage in rheumatoid arthritis (RA). Eukaryotic elongation factor-2 kinase (eEF2K) is a negative regulator of protein synthesis and has been shown to play an important role in regulating various cellular processes and promoting glycolysis in tumor cells. However, the role of eEF2K in regulating the pathogenic FLS behaviors is unknown. METHODS: A specific inhibitor of eEF2K, NH125, and siRNA were used to evaluate the role of eEF2K on RA FLSs in vitro. Collagen-induced arthritis (CIA) mice were used to evaluate the in vivo effect of eEF2K. Cell migration, invasion of RA FLSs were assessed by transwell or wound healing assays. Relative changes of cytokines were analyzed by quantitative real-time PCR, western blot and ELISA. RESULTS: Herein, we found an increased expression of eEF2K in synovial tissues and FLSs of RA patients. eEF2K knockdown by siRNA or treatment with NH125, an inhibitor of eEF2K, significantly reduced inflammation, migration/invasion, glucose uptake and lactate productions. eEF2K knockdown suppressed TNF-α-induced activation of NF-κB and AKT pathways in RA FLSs. Lactate reversed the inhibitory effect of eEF2K knockdown on inflammation and migration of RA FLSs. Moreover, lactate was also involved in eEF2K-mediated activation of NF-κB and AKT. NH125 treatment attenuated the severity of arthritis in collagen-induced arthritis mice. CONCLUSION: eEF2K inhibition suppressed glycolysis and aggressive behaviors of RA FLS, which indicated that targeting eEF2K may be a new strategy for the treatment of RA. Dove 2022-03-10 /pmc/articles/PMC8922331/ /pubmed/35300214 http://dx.doi.org/10.2147/JIR.S337620 Text en © 2022 Chen et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Chen, Dongying
Cai, Xiaoyan
Ouyang, Hui
Yuan, Shiwen
Wang, Xiaodong
Lin, Lian
Chen, Zhiqing
Huang, Mingcheng
Increased eEF2K Promotes Glycolysis and Aggressive Behaviors of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis
title Increased eEF2K Promotes Glycolysis and Aggressive Behaviors of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis
title_full Increased eEF2K Promotes Glycolysis and Aggressive Behaviors of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis
title_fullStr Increased eEF2K Promotes Glycolysis and Aggressive Behaviors of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis
title_full_unstemmed Increased eEF2K Promotes Glycolysis and Aggressive Behaviors of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis
title_short Increased eEF2K Promotes Glycolysis and Aggressive Behaviors of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis
title_sort increased eef2k promotes glycolysis and aggressive behaviors of fibroblast-like synoviocytes in rheumatoid arthritis
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8922331/
https://www.ncbi.nlm.nih.gov/pubmed/35300214
http://dx.doi.org/10.2147/JIR.S337620
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