PMID- 37060808 OWN - NLM STAT- MEDLINE DCOM- 20230601 LR - 20230601 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 119 DP - 2023 Jun TI - CX-4945 inhibits fibroblast-like synoviocytes functions through the CK2-p53 axis to reduce rheumatoid arthritis disease severity. PG - 110163 LID - S1567-5769(23)00484-8 [pii] LID - 10.1016/j.intimp.2023.110163 [doi] AB - Fibroblast-like synoviocytes (FLS) mediate many pathological processes in rheumatoid arthritis (RA), including pannus formation, bone erosion, and inflammation. RA FLS have unique aggressive phenotypes and exhibit several tumor cell-like characteristics, including hyperproliferation, excessive migration and invasion. Casein kinase 2 (CK2) is reportedly overexpressed in numerous tumor types, and targeted inhibition of CK2 has therapeutic benefits for tumors. However, the expression level of CK2 and its functions in RA FLS remain unclear. Herein, we aimed to elucidate whether CK2 is responsible for the aggressive phenotypes of RA FLS and whether targeted therapy can alleviate the severity of RA. We found that CK2 subunits were elevated in RA FLS compared with osteoarthritis FLS, and the activity of CK2 also markedly increased in RA FLS. Targeted inhibition of CK2 using CX-4945 suppressed RA FLS proliferation through cell cycle arrest. Cell migration and invasion were also inhibited by CX-4945 treatment. Moreover, CX-4945 reduced Interleukin-6 (IL-6), CC motif chemokine ligand 2 (CCL2) and Matrix metalloproteinase-3 (MMP-3) secretion in RA FLS. Further proteomic investigation revealed that p53 signaling pathway significantly changes after CX-4945 treatment in RA FLS. The siRNA-mediated p53 knockdown partly abolished the anti-proliferation and reduced IL-6, MMP-3 secretion effects of CX-4945. Furthermore, CX-4945 administration alleviates arthritis severity in CIA mice. Collectively, our results demonstrated the abnormal elevation of CK2 and its positive association with abnormal phenotypes in RA FLS. Our novel findings suggest the possible therapeutic potential of CX-4945 for RA. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Luo, Yanping AU - Luo Y AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. FAU - Lei, Yunxuan AU - Lei Y AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. FAU - Guo, Xin AU - Guo X AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. FAU - Zhu, Dehao AU - Zhu D AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. FAU - Zhang, Haiyang AU - Zhang H AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. FAU - Guo, Zizhen AU - Guo Z AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. FAU - Xu, Zichong AU - Xu Z AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. FAU - Zhao, Hanqing AU - Zhao H AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. FAU - Xi, Yebin AU - Xi Y AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. FAU - Peng, Xiaochun AU - Peng X AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. FAU - Xiao, Lianbo AU - Xiao L AD - Department of Joint Surgery, Guanghua Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai 200052, China. FAU - Wang, Zhaojun AU - Wang Z AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. Electronic address: zjwang@sjtu.edu.cn. FAU - Niu, Xiaoyin AU - Niu X AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. Electronic address: niuxiaoyin@163.com. FAU - Chen, Guangjie AU - Chen G AD - Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Shanghai 200025, China. Electronic address: guangjie_chen@163.com. LA - eng PT - Journal Article DEP - 20230413 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - EC 2.7.11.1 (Casein Kinase II) RN - C6RWP0N0L2 (silmitasertib) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - 0 (Tumor Suppressor Protein p53) RN - 0 (Interleukin-6) SB - IM MH - Mice MH - Animals MH - *Synoviocytes MH - Casein Kinase II/metabolism/pharmacology/therapeutic use MH - Matrix Metalloproteinase 3/metabolism MH - Tumor Suppressor Protein p53/metabolism MH - Interleukin-6/metabolism MH - Proteomics MH - Cell Proliferation MH - Cells, Cultured MH - *Arthritis, Rheumatoid/metabolism MH - Fibroblasts MH - Patient Acuity MH - Synovial Membrane/pathology OTO - NOTNLM OT - CX-4945 OT - Casein kinase 2 OT - Fibroblast-like synoviocytes OT - Rheumatoid arthritis OT - p53 signaling pathway COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/04/16 06:00 MHDA- 2023/06/01 06:42 CRDT- 2023/04/15 18:07 PHST- 2023/02/21 00:00 [received] PHST- 2023/03/28 00:00 [revised] PHST- 2023/04/05 00:00 [accepted] PHST- 2023/06/01 06:42 [medline] PHST- 2023/04/16 06:00 [pubmed] PHST- 2023/04/15 18:07 [entrez] AID - S1567-5769(23)00484-8 [pii] AID - 10.1016/j.intimp.2023.110163 [doi] PST - ppublish SO - Int Immunopharmacol. 2023 Jun;119:110163. doi: 10.1016/j.intimp.2023.110163. Epub 2023 Apr 13.