Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells.
Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells.
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胶质母细胞瘤细胞中HSP90靶向的ANTP-TPR杂交肽诱导的细胞毒性的分子机制。
DOI：
10.1186/1476-4598-11-59
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发表时间：
2012-08-22
期刊：
影响因子：
37.3
通讯作者：
Kawakami K
中科院分区：
文献类型：
--
作者：
Horibe T;Torisawa A;Kohno M;Kawakami K
热休克蛋白90（Hsp 90）对应激条件下的细胞存活至关重要，并且结合客户蛋白以帮助蛋白质稳定、多肽跨细胞膜的易位以及蛋白质从聚集体的回收。因此，Hsp 90已成为治疗癌症的重要靶点。我们以前报道过，新的Antp-TPR杂合肽，它可以抑制热休克蛋白90与啤酒花的TPR 2A结构域的相互作用，诱导选择性细胞毒活性，区分正常和癌细胞在体外和体内。在这项研究中，我们研究了Antp-TPR杂合肽在胶质母细胞瘤（GB）细胞系中的功能性癌细胞杀伤机制。证明Antp-TPR肽通过Hsp 90客户蛋白如p53、Akt、CDK 4和cRaf的损失在GB细胞中诱导有效的细胞毒性活性。Antp-TPR也不诱导Hsp 70和Hsp 90蛋白的上调，尽管Hsp 90的小分子抑制剂17-AAG诱导这些蛋白的上调。同时发现Antp-TPR肽在内质网应激条件下增加了内质网未折叠蛋白的反应，并增强了该杂合肽对GB细胞的细胞毒活性。这些结果表明，通过Antp-TPR靶向Hsp 90可能是选择性杀死癌细胞的有吸引力的方法，因为没有其他靶向Hsp 90的化合物显示选择性细胞毒性活性。Antp-TPR可能为癌症的治疗提供有效和选择性的治疗选择。
Heat-shock protein 90 (Hsp90) is vital to cell survival under conditions of stress, and binds client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes, and recovery of proteins from aggregates. Therefore, Hsp90 has emerged as an important target for the treatment of cancer. We previously reported that novel Antp-TPR hybrid peptide, which can inhibit the interaction of Hsp90 with the TPR2A domain of Hop, induces selective cytotoxic activity to discriminate between normal and cancer cells both in vitro and in vivo. In this study, we investigated the functional cancer-cell killing mechanism of Antp-TPR hybrid peptide in glioblastoma (GB) cell lines. It was demonstrated that Antp-TPR peptide induced effective cytotoxic activity in GB cells through the loss of Hsp90 client proteins such as p53, Akt, CDK4, and cRaf. Antp-TPR also did not induce the up-regulation of Hsp70 and Hsp90 proteins, although a small-molecule inhibitor of Hsp90, 17-AAG, induced the up-regulation of these proteins. It was also found that Antp-TPR peptide increased the endoplasmic reticulum unfolded protein response, and the cytotoxic activity of this hybrid peptide to GB cells in the endoplasmic reticulum stress condition. These results show that targeting of Hsp90 by Antp-TPR could be an attractive approach to selective cancer-cell killing because no other Hsp90-targeted compounds show selective cytotoxic activity. Antp-TPR might provide potent and selective therapeutic options for the treatment of cancer.
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影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
影响因子：
50.3
作者：
Isaacs, JS;Xu, WP;Neckers, L
通讯作者：
Neckers, L
影响因子：
3.5
作者：
Falsone, SF;Gesslbauer, B;Kungl, AJ
通讯作者：
Kungl, AJ
影响因子：
16
作者：
Leu, J. I-Ju;Pimkina, Julia;Frank, Amanda;Murphy, Maureen E.;George, Donna L.
通讯作者：
George, Donna L.
DOI：
10.1158/1541-7786.mcr-11-0019
发表时间：
2011-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Leu JI;Pimkina J;Pandey P;Murphy ME;George DL
通讯作者：
George DL