Pexmetinib suppresses osteoclast formation and breast cancer induced osteolysis via P38/STAT3 signal pathway.
Pexmetinib suppresses osteoclast formation and breast cancer induced osteolysis via P38/STAT3 signal pathway.
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DOI：
10.1016/j.jbo.2022.100439
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发表时间：
2022-08
影响因子：
3.4
通讯作者：
Jiang, Chao
中科院分区：
文献类型：
--
作者：
Jie, Zhiwei;Wang, Shiyu;Ma, Qingliang;Shen, Yang;Zhao, Xiangde;Yu, Hejun;Xie, Ziang;Jiang, Chao
Pexmetinib在体外抑制破骨细胞生成。Pexmetinib在体外抑制乳腺癌的迁移和侵袭。Pexmetinib治疗在体内减弱乳腺癌诱导的骨质溶解。乳腺癌骨转移可导致一系列骨相关事件，严重影响患者的生活质量。Pexmetinib是一种新型的p38丝裂原活化蛋白激酶（p38）抑制剂，已在骨髓增生异常综合征的I期临床试验中进行了评估，但Pexmetinib对乳腺癌诱导的骨质溶解的影响尚未探索。在此，我们发现Pexmetinib在体外抑制核因子-κB受体激活剂配体诱导的破骨细胞形成和骨吸收。Pexmetinib抑制p38介导的信号转导和转录激活因子3（STAT 3），其直接调节活化T细胞核因子1（NFATc 1）的转录，导致破骨细胞形成减少。此外，Pexmetinib通过抑制p38介导的STAT 3激活和基质金属蛋白酶（MMPs）表达在体外乳腺癌细胞中发挥抗肿瘤作用。此外，Pexmetinib在体内抑制乳腺癌相关的骨质溶解。这些结果表明，Pexmetinib可能是一种有前途的药物，用于治疗乳腺癌引起的骨质溶解。
Pexmetinib inhibited osteoclastogenesis in vitro. Pexmetinib inhibited breast cancer migration and invasion in vitro. Pexmetinib treatment attenuated breast cancer induced osteolysis in vivo. Breast cancer metastases to the bone can lead to a series of bone-related events that seriously affect the quality of life. Pexmetinib, a novel p38 mitogen-activated protein kinase (p38) inhibitor that has been evaluated in phase I clinical trials for myelodysplastic syndrome, but the effects of Pexmetinib on breast cancer induced osteolysis haven’t been explored. Here, we found that Pexmetinib inhibited receptor activator of nuclear factor-κB ligand-induced osteoclast formation and bone resorption in vitro. Pexmetinib suppressed p38-mediated signal transducer and activator of transcription 3 (STAT3), which direct regulated transcription of the nuclear factor of activated T cells 1 (NFATc1), leading to reduced osteoclast formation. Moreover, Pexmetinib exerted anti-tumor effects in breast cancer cells in vitro via suppressing p38-mediated STAT3 activation and matrix metalloproteinases (MMPs) expression. Furthermore, Pexmetinib suppressed breast cancer-associated osteolysis in vivo. These results suggest that Pexmetinib may be a promising drug for the treatment of breast cancer-induced osteolysis.
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影响因子：
8
作者：
Niu, GL;Wright, KL;Yu, H
通讯作者：
Yu, H
DOI：
10.1073/pnas.0404100101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Dechow, TN;Pedranzini, L;Bromberg, JF
通讯作者：
Bromberg, JF
影响因子：
11.2
作者：
Min, Yongfen;Ren, Xiubao;Lin, P. Charles
通讯作者：
Lin, P. Charles
影响因子：
6.4
作者：
Banerjee K;Resat H
通讯作者：
Resat H
影响因子：
11.2
作者：
Bachegowda L;Morrone K;Winski SL;Mantzaris I;Bartenstein M;Ramachandra N;Giricz O;Sukrithan V;Nwankwo G;Shahnaz S;Bhagat T;Bhattacharyya S;Assal A;Shastri A;Gordon-Mitchell S;Pellagatti A;Boultwood J;Schinke C;Yu Y;Guha C;Rizzi J;Garrus J;Brown S;Wollenberg L;Hogeland G;Wright D;Munson M;Rodriguez M;Gross S;Chantry D;Zou Y;Platanias L;Burgess LE;Pradhan K;Steidl U;Verma A
通讯作者：
Verma A