Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells
Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells
复制标题
DOI：
10.1016/j.canlet.2015.07.006
复制
发表时间：
2015-10-01
期刊：
影响因子：
9.7
通讯作者：
Cirone, Mara
中科院分区：
文献类型：
--
作者：
Granato, Marisa;Chiozzi, Barbara;Cirone, Mara
PEL细胞依赖于STAT 3的组成性激活来存活，因此AG 490对其的抑制导致凋亡性细胞死亡。在这项研究中，我们发现AG 490的细胞毒活性与HSP 70及其主调节因子HSF 1的减少相关，基于敲低实验，发现HSF 1在PEL细胞中发挥促生存作用。为了抵消由HSF 1/HSP 70下调介导的促死亡效应，AG 490诱导了完全的自噬，其抑制增强了其对PEL细胞的细胞毒性效应。AG 490以及HSF 1 siRNA降低了Mcl-1的表达，Mcl-1是Bcl-2家族成员，其负调节细胞凋亡和自噬。这些结果表明，STAT 3抑制，通过下调HSF 1/HSP 70的表达，减少Mcl-1，并导致细胞凋亡和自噬诱导的PEL细胞。(C)2015爱思唯尔爱尔兰有限公司版权所有。
PEL cells relay on the constitutive activation of STAT3 for their survival, thus its inhibition by AG490 leads to apoptotic cell death. In this study, we found that the cytotoxic activity of AG490 correlated with the reduction of HSP70 and its master regulator HSF1 that, based on knocking-down experiments, was found to play a pro-survival role in PEL cells. To counteract the pro-death effect mediated by HSF1/HSP70 down-regulation, AG490 induced a complete autophagy, whose inhibition potentiated its cytotoxic effect against PEL cells. AG490 as well as HSF1 siRNA reduced the expression of Mcl-1, a Bcl-2 family member that negatively regulates apoptosis and autophagy. These results suggest that STAT3 inhibition, by down-regulating the expression of HSF1/HSP70, reduces Mcl-1 and leads to both apoptosis and autophagy induction in PEL cells. (C) 2015 Elsevier Ireland Ltd. All rights reserved.