BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling.
BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling.
复制标题
BTK 通过激活 AKT/P27/Rb 信号传导抑制骨髓瘤细胞衰老
DOI：
10.18632/oncotarget.18096
复制
发表时间：
2017-08-22
期刊：
影响因子：
--
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Gu C;Peng H;Lu Y;Yang H;Tian Z;Yin G;Zhang W;Lu S;Zhang Y;Yang Y
我们先前探讨了BTK在维持多发性骨髓瘤干细胞（MMSC）自我更新和耐药性中的作用。在这里，我们研究了BTK抑制MM细胞衰老的升高，这是一种不可逆的细胞生长停滞状态。我们首先通过免疫组织化学（IHC）发现与正常对照相比，MM样品中BTK的表达增加，并且在原代样品中有显著的染色体获得。此外，BTK高表达MM患者与总体治疗2（TT 2）和TT 3队列中的不良结局相关。通过β-半乳糖苷酶（SA-b-gal）染色，通过shRNA敲低BTK表达诱导MM细胞衰老，通过细胞周期染色诱导细胞生长停滞，并降低克隆形成，同时迫使MM细胞中BTK表达消除这些特征。我们还在小鼠胚胎成纤维细胞（MEFs）中验证了这一特征，这表明在体外连续培养后，BTK表达升高可抵抗MEFs衰老。进一步的机制研究表明，BTK激活AKT信号通路，导致P27表达下调，抑制RB活性，而AKT抑制剂LY 294002克服了BTK过表达诱导的细胞衰老抗性。最后，我们证明了BTK抑制剂CGI-1746在体内诱导MM细胞衰老、集落减少和致瘤性抑制。综上所述，我们提出了BTK介导MM生长的一种新机制，BTK抑制剂在体内和体外都具有很大的潜力，表明BTK是MM有希望的治疗靶点。
We previously explored the role of BTK in maintaining multiple myeloma stem cells (MMSCs) self-renewal and drug-resistance. Here we investigated the elevation of BTK suppressing MM cellular senescence, a state of irreversible cellular growth arrest. We firstly discovered that an increased expression of BTK in MM samples compared to normal controls by immunohistochemistry (IHC), and significant chromosomal gain in primary samples. In addition, BTK high-expressing MM patients are associated with poor outcome in both Total Therapy 2 (TT2) and TT3 cohorts. Knockdown BTK expression by shRNA induced MM cellular senescence using β-galactosidase (SA-b-gal) staining, cell growth arrest by cell cycle staining and decreased clonogenicity while forcing BTK expression in MM cells abrogated these characteristics. We also validated this feature in mouse embryonic fibroblast cells (MEFs), which showed that elevated BTK expression was resistant to MEF senescence after serial cultivation in vitro. Further mechanism study revealed that BTK activated AKT signaling leading to down-regulation of P27 expression and hindered RB activity while AKT inhibitor, LY294002, overcame BTK-overexpression induced cellular senescence resistance. Eventually we demonstrated that BTK inhibitor, CGI-1746, induced MM cellular senescence, colony reduction and tumorigenecity inhibition in vivo. Summarily, we designate a novel mechanism of BTK in mediating MM growth, and BTK inhibitor is of great potential in vivo and in vitro suggesting BTK is a promising therapeutic target for MM.
登录
查看更多内容
影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
--
作者：
Fristedt Duvefelt C;Lub S;Agarwal P;Arngården L;Hammarberg A;Maes K;Van Valckenborgh E;Vanderkerken K;Jernberg Wiklund H
通讯作者：
Jernberg Wiklund H
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS
DOI：
10.1016/j.biocel.2015.08.005
发表时间：
2015-11-01
影响因子：
4
作者：
Hnit, Su Su Thae;Xie, Chanlu;Dong, Qihan
通讯作者：
Dong, Qihan
影响因子：
4.4
作者：
Middendorp, S;Dingjan, GM;Hendriks, RW
通讯作者：
Hendriks, RW