下调和上调
细胞凋亡
生物
癌症研究
Hsp90抑制剂
细胞生物学
程序性细胞死亡
信号转导
热休克蛋白
热休克蛋白90
生物化学
基因
作者
Koshi Akahane,Takaomi Sanda,Marc R. Mansour,Thomas Radimerski,Daniel J. DeAngelo,David M. Weinstock,A. Thomas Look
出处
期刊:Leukemia
[Springer Nature]
日期:2015-08-12
卷期号:30 (1): 219-228
被引量:33
摘要
We previously found that tyrosine kinase 2 (TYK2) signaling through its downstream effector phospho-STAT1 acts to upregulate BCL2, which in turn mediates aberrant survival of T-cell acute lymphoblastic leukemia (T-ALL) cells. Here we show that pharmacologic inhibition of heat shock protein 90 (HSP90) with a small-molecule inhibitor, NVP-AUY922 (AUY922), leads to rapid degradation of TYK2 and apoptosis in T-ALL cells. STAT1 protein levels were not affected by AUY922 treatment, but phospho-STAT1 (Tyr-701) levels rapidly became undetectable, consistent with a block in signaling downstream of TYK2. BCL2 expression was downregulated after AUY922 treatment, and although this effect was necessary for AUY922-induced apoptosis, it was not sufficient because many T-ALL cell lines were resistant to ABT-199, a specific inhibitor of BCL2. Unlike ABT-199, AUY922 also upregulated the proapoptotic proteins BIM and BAD, whose increased expression was required for AUY922-induced apoptosis. Thus, the potent cytotoxicity of AUY922 involves the synergistic combination of BCL2 downregulation coupled with upregulation of the proapoptotic proteins BIM and BAD. This two-pronged assault on the mitochondrial apoptotic machinery identifies HSP90 inhibitors as promising drugs for targeting the TYK2-mediated prosurvival signaling axis in T-ALL cells.
科研通智能强力驱动
Strongly Powered by AbleSci AI