Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones.
Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones.
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DOI：
10.1007/s13402-018-0397-1
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Aguilera RJ
中科院分区：
文献类型：
--
作者：
Contreras L;Calderon RI;Varela-Ramirez A;Zhang HY;Quan Y;Das U;Dimmock JR;Skouta R;Aguilera RJ
此前，含有哌啶酮结构的化合物已被证明对癌细胞具有高度细胞毒性。最近，我们发现哌啶酮化合物P2对人乳腺癌来源的细胞表现出有效的抗肿瘤活性。在这里，我们的目的是评估两个哌啶酮化合物，P1和P2，其对人白血病/淋巴瘤衍生细胞的潜在抗肿瘤活性。使用MTS、膜联蛋白V-FITC/PI和线粒体膜电位多色测定评价细胞毒性和凋亡诱导，以确认哌啶酮化合物的作用模式。使用AmpliSeq分析评估化合物P1和P2处理对基因表达的影响，随后通过RT-qPCR和蛋白质印迹证实。我们发现，两个相关的哌啶酮化合物P1和P2选择性地杀死白血病/淋巴瘤细胞测试纳摩尔浓度通过诱导的内在凋亡途径，证明了线粒体去极化和caspase-3激活。基于AmpliSeq的化合物P1和P2对HL-60急性白血病细胞的作用的转录组分析揭示了数百个基因的差异表达，其中358个被发现受到两者的影响。额外的途径分析表明，显着数量的共同基因与未折叠的蛋白质反应，这意味着可能的作用，这两种化合物在诱导蛋白毒性应激。随后的转录组数据分析显示，P1和P2诱导类似的基因表达变化作为其他众所周知的蛋白酶体抑制剂。最后，我们发现，Noxa，蛋白酶体抑制剂的活性的重要介质，在mRNA和蛋白质水平显着上调，表明P1和P2诱导的细胞毒性机制中可能的作用。我们的数据表明P1和P2对白血病/淋巴瘤细胞的细胞毒活性是由蛋白酶体抑制介导的，导致促凋亡途径的激活。
Previously, compounds containing a piperidone structure have been shown to be highly cytotoxic to cancer cells. Recently, we found that the piperidone compound P2 exhibits a potent anti-neoplastic activity against human breast cancer-derived cells. Here, we aimed to evaluate two piperidone compounds, P1 and P2, for their potential anti-neoplastic activity against human leukemia/lymphoma-derived cells. Cytotoxicity and apoptosis induction were evaluated using MTS, annexin V-FITC/PI and mitochondrial membrane potential polychromatic assays to confirm the mode of action of the piperidone compounds. The effects of compound P1 and P2 treatment on gene expression were assessed using AmpliSeq analysis and, subsequently, confirmed by RT-qPCR and Western blotting. We found that the two related piperidone compounds P1 and P2 selectively killed the leukemia/lymphoma cells tested at nanomolar concentrations through induction of the intrinsic apoptotic pathway, as demonstrated by mitochondrial depolarization and caspase-3 activation. AmpliSeq-based transcriptome analyses of the effects of compounds P1 and P2 on HL-60 acute leukemia cells revealed a differential expression of hundreds of genes, 358 of which were found to be affected by both. Additional pathway analyses revealed that a significant number of the common genes were related to the unfolded protein response, implying a possible role of the two compounds in the induction of proteotoxic stress. Subsequent analyses of the transcriptome data revealed that P1 and P2 induced similar gene expression alterations as other well-known proteasome inhibitors. Finally, we found that Noxa, an important mediator of the activity of proteasome inhibitors, was significantly upregulated at both the mRNA and protein levels, indicating a possible role in the cytotoxic mechanism induced by P1 and P2. Our data indicate that the cytotoxic activity of P1 and P2 on leukemia/lymphoma cells is mediated by proteasome inhibition, leading to activation of pro-apoptotic pathways.
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影响因子：
5.7
作者：
Hideshima T;Richardson PG;Anderson KC
通讯作者：
Anderson KC
影响因子：
4.8
作者：
Fribley, Andrew M.;Evenchik, Benjamin;Wang, Cun-Yu
通讯作者：
Wang, Cun-Yu
DOI：
10.1007/s13402-016-0297-1
发表时间：
2017-03
期刊：
Cellular oncology (Dordrecht, Netherlands)
影响因子：
--
作者：
Chavez-Gonzalez A;Bakhshinejad B;Pakravan K;Guzman ML;Babashah S
通讯作者：
Babashah S
影响因子：
--
作者：
Downey, Sondra L;Florea, Bogdan I;Kisselev, Alexei F
通讯作者：
Kisselev, Alexei F
影响因子：
6.7
作者：
Das, Umashankar;Alcorn, Jane;Dimmock, Jonathan R.
通讯作者：
Dimmock, Jonathan R.