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首页> 外文期刊>Apoptosis >DAPK plays an important role in panobinostat-induced autophagy and commits cells to apoptosis under autophagy deficient conditions
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DAPK plays an important role in panobinostat-induced autophagy and commits cells to apoptosis under autophagy deficient conditions

机译：DAPK在panobinostat诱导的自噬中起重要作用，并在自噬不足条件下使细胞凋亡

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The histone deacetylase inhibitor (HDACi) LBH589 has been verified as an effective anticancer agent. The identification and characterization of new targets for LBH589 action would further enhance our understanding of the molecular mechanisms involved in HDACi therapy. The role of the tumor suppressor death-associated protein kinase (DAPK) in LBH589-induced cytotoxicity has not been investigated to date. Stable DAPK knockdown (shRNA) and DAPK overexpressing (DAPK+++) cell lines were generated from HCT116 wildtype colon cancer cells. LBH589 inhibited cell proliferation, reduced the long-term survival, and up-regulated and activated DAPK in colorectal cancer cells. Moreover, LBH589 significantly suppressed the growth of colon tumor xenografts and in accordance with the in vitro studies, increased DAPK levels were detected immunohistochemically. LBH589 induced a DAPK-dependent autophagy as assessed by punctuate accumulation of LC3-II, the formation of acidic vesicular organelles, and degradation of p62 protein. LBH589-induced autophagy seems to be predominantly caused by DAPK protein interactions than by its kinase activity. Caspase inhibitor zVAD increased autophagosome formation, decreased the cleavage of caspase 3 and PARP but didn’t rescue the cells from LBH589-induced cell death in crystal violet staining suggesting both caspase-dependent as well as caspase-independent apoptosis pathways. Pre-treatment with the autophagy inhibitor Bafilomycin A1 caused caspase 3-mediated apoptosis in a DAPK-dependent manner. Altogether our data suggest that DAPK induces autophagy in response to HDACi-treatment. In autophagy deficient cells, DAPK plays an essential role in committing cells to HDACi-induced apoptosis.
机译：组蛋白脱乙酰基酶抑制剂（HDACi）LBH589已被证实是有效的抗癌药。 LBH589作用的新靶标的鉴定和表征将进一步增强我们对HDACi治疗涉及的分子机制的了解。迄今为止，尚未研究肿瘤抑制因子死亡相关蛋白激酶（DAPK）在LBH589诱导的细胞毒性中的作用。从HCT116野生型结肠癌细胞中产生了稳定的DAPK敲低（shRNA）和DAPK过表达（DAPK +++）细胞系。 LBH589在结肠直肠癌细胞中抑制细胞增殖，降低长期存活率，并上调和激活DAPK。此外，LBH589显着抑制结肠肿瘤异种移植物的生长，根据体外研究，免疫组化检测到DAPK水平升高。通过LC3-II的点状积累，酸性水泡细胞器的形成和p62蛋白的降解评估，LBH589诱导了DAPK依赖性自噬。 LBH589诱导的自噬似乎主要由DAPK蛋白相互作用引起，而不是由其激酶活性引起。半胱天冬酶抑制剂zVAD可增加自噬体的形成，减少半胱天冬酶3和PARP的裂解，但不能通过结晶紫染色使细胞从LBH589诱导的细胞死亡中解救出来，这提示了caspase依赖性和caspase依赖性凋亡途径。用自噬抑制剂Bafilomycin A1预处理以DAPK依赖性方式引起caspase 3介导的细胞凋亡。总体而言，我们的数据表明DAPK响应HDACi治疗诱导自噬。在自噬缺陷细胞中，DAPK在使细胞发生HDACi诱导的细胞凋亡中起着至关重要的作用。

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