Premium
Chemical inhibition of HSP90 inhibits TNF‐α mediated proliferation and induces apoptosis in human rheumatoid arthritis fibroblast‐like synoviocytes
Author(s) -
Yang Bin,
Liu Xiangru,
Liang Yongqian,
Li Yue
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.27549
Subject(s) - geldanamycin , apoptosis , hsp90 , tumor necrosis factor alpha , cytochrome c , mapk/erk pathway , cancer research , microbiology and biotechnology , signal transduction , chemistry , fibroblast , caspase 3 , cell growth , p38 mitogen activated protein kinases , poly adp ribose polymerase , programmed cell death , biology , immunology , biochemistry , polymerase , heat shock protein , in vitro , enzyme , gene
Rheumatoid arthritis fibroblast‐like synoviocytes (RAFLS) proliferate abnormally and resist apoptosis. Geldanamycin (GA) and other HSP90 inhibitors have emerged as promising therapeutic agents that inhibited cancer cell growth. In this study, we explored the effects of HSP90 inhibitor, GA, on tumor necrosis factor (TNF)‐α‐induced proliferation and apoptosis of RAFLS, and the underlying mechanism. Human RAFLS was isolated from the knee joints of patients with RA and subjected to TNF‐α treatment in combination of various concentration of GA. We found that GA dose‐dependently inhibited TNF‐α‐induced RAFLS proliferation as measured, but promoted RAFLS apoptosis. Further mechanistic study identified that GA dose‐dependently attenuated TNF‐α‐mediated activation of mitogen‐activated protein kinases (MAPKs) and nuclear factor‐kappa B (NF‐κB) pathways, both of which are involved in TNF‐α‐mediated RAFLS proliferation. Moreover, GA‐induced apoptosis and mitochondrial damage of RAFLS, as evidenced by increased Bax/Bcl‐2 ratio and mitochondrial cytochrome c release, and enhanced cleavages of caspase‐3, caspase‐9, and poly‐(ADP‐ribose) polymerase. Collectively, our results revealed that chemical inhibition of HSP90 by GA suppressed TNF‐α‐induced proliferation of RAFLSs through the MAPK and NF‐κB signaling pathways and induces RAFLS apoptosis via mitochondria‐dependent pathway. These findings demonstrated for the first time that HSP90 inhibition in RAFLS could be therapeutic beneficial for RA.