Survivin inhibitor YM155 induces mitochondrial dysfunction, autophagy, DNA damage and apoptosis in Bcl-xL silenced glioma cell lines.
Survivin inhibitor YM155 induces mitochondrial dysfunction, autophagy, DNA damage and apoptosis in Bcl-xL silenced glioma cell lines.
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DOI：
10.1002/mc.22587
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发表时间：
2017-04
影响因子：
4.6
通讯作者：
Pollack IF
中科院分区：
文献类型：
--
作者：
Jane EP;Premkumar DR;Sutera PA;Cavaleri JM;Pollack IF
由于抗凋亡蛋白Bcl-xL在胶质瘤中过度表达，人们可能会认为抑制或沉默该基因会促进肿瘤细胞的杀伤。然而，我们的研究表明，这种方法具有有限的独立活性，但可能在其他治疗干预措施的反应中倾向于细胞凋亡诱导。为了解决这个问题，我们在Bcl-xL沉默细胞中使用一组信号抑制剂和化疗药物进行了药理学筛选。尽管一系列受体酪氨酸激酶抑制剂、PKC抑制剂、Src家族成员、JAK/STAT、组蛋白去乙酰化酶、PI3K/Akt/mTOR通路、MAP激酶、CDK、热休克蛋白、蛋白酶体加工和各种常规化疗药物都能诱导有限的细胞凋亡，但我们发现survivin抑制剂YM155能显著增强Bcl-xL沉默细胞的凋亡。在Bcl-xL沉默细胞中，YM155增加了细胞色素c、smac/DIABLO和凋亡诱导因子的释放，促进了线粒体膜电位的丧失、Bax的激活、LC3-II向自噬体的募集和凋亡。我们还发现了另一种增加细胞凋亡的机制，这是由于Rad51抑制介导的DNA双链断裂修复的破坏和γ - h2ax积累的增强。总之，我们的观察结果可能为Bcl-xL和survivin抑制之间的联系提供新的见解，为胶质瘤的新疗法的发展提供新的见解。
Because the anti-apoptotic protein Bcl-xL is overexpressed in glioma, one might expect that inhibiting or silencing this gene would promote tumor cell killing. However, our studies have shown that this approach has limited independent activity, but may tip the balance in favor of apoptosis induction in response to other therapeutic interventions. To address this issue, we performed a pharmacological screen using a panel of signaling inhibitors and chemotherapeutic agents in Bcl-xL silenced cells. Although limited apoptosis induction was observed with a series of inhibitors for receptor tyrosine kinases, PKC inhibitors, Src family members, JAK/STAT, histone deacetylase, the PI3K/Akt/mTOR pathway, MAP kinase, CDK, heat shock proteins, proteasomal processing, and various conventional chemotherapeutic agents, we observed a dramatic potentiation of apoptosis in Bcl-xL silenced cells with the survivin inhibitor, YM155. Treatment with YM155 increased the release of cytochrome c, smac/DIABLO and apoptosis inducing-factor, and promoted loss of mitochondrial membrane potential, activation of Bax, recruitment of LC3-II to the autophagosomes and apoptosis in Bcl-xL silenced cells. We also found an additional mechanism for the augmentation of apoptosis due to abrogation of DNA double-strand break repair mediated by Rad51 repression and enhanced accumulation of γH2AX. In summary, our observations may provide a new insight into the link between Bcl-xL and survivin inhibition for the development of novel therapies for glioma.
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DOI：
10.2174/1568011033482396
发表时间：
2003-07-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
Bettaieb, Ali;Dubrez-Daloz, Laurence;Solary, Eric
通讯作者：
Solary, Eric
影响因子：
4.1
作者：
Eno, Colins O.;Zhao, Guoping;Li, Chi
通讯作者：
Li, Chi
影响因子：
4.8
作者：
Han, Jie;Hou, Wen;Rabinowich, Hannah
通讯作者：
Rabinowich, Hannah
影响因子：
3.3
作者：
Guensberg, P;Wacheck, V;Jansen, B
通讯作者：
Jansen, B
DOI：
10.1124/jpet.114.212910
发表时间：
2014-07-01
影响因子：
3.5
作者：
Jane, Esther P.;Premkumar, Daniel R.;Pollack, Ian F.
通讯作者：
Pollack, Ian F.