Inhibition of heat shock protein 27 (HspB1) tumorigenic functions by peptide aptamers
Inhibition of heat shock protein 27 (HspB1) tumorigenic functions by peptide aptamers
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DOI：
10.1038/onc.2011.73
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发表时间：
2011-08-01
期刊：
影响因子：
8
通讯作者：
Diaz-Latoud, C.
中科院分区：
文献类型：
--
作者：
Gibert, B.;Hadchity, E.;Diaz-Latoud, C.
人热休克蛋白27（Hsp 27，HspB 1）是一种抗凋亡蛋白，具有致瘤性和转移性，是多种肿瘤的主要治疗靶点。热休克蛋白27的生物化学特性依赖于结构寡聚体和动态组织。通过小干扰RNA的下调或显性负突变体的抑制已经证明了它们对抵消Hsp 27的抗凋亡和保护特性的有效性。在这项研究中，我们报告的分离和表征的热休克蛋白27靶向分子干扰其结构组织。使用肽适体（PA）的策略，我们分离的PA，专门与热休克蛋白27，而不是与其他成员的小热休克蛋白家族。在哺乳动物细胞培养物中，PA的表达扰乱了热休克蛋白27的二聚化和寡聚化，并作为该蛋白的抗凋亡和细胞保护活性的负调节剂。在免疫功能低下小鼠中分析SQ 20 B细胞异种移植物的进一步研究表明，PA通过细胞周期阻滞强烈降低肿瘤发展。我们的数据表明，PA可以提供一个潜在的工具，以制定战略，发现热休克蛋白27的化学抑制剂。Oncogene（2011）30，3672-3681; doi：10.1038/onc.2011.73; 2011年3月21日在线发表
Human heat shock protein 27 (Hsp27, HspB1) is an antiapoptotic protein characterized for its tumorigenic and metastatic properties, and now referenced as a major therapeutic target in many types of cancer. Hsp27 biochemical properties rely on a structural oligomeric and dynamic organization. Downregulation by small interfering RNA or inhibition with dominant-negative mutant have proven their efficiency to counteract the antiapoptotic and protective properties of Hsp27. In this study, we report the isolation and characterization of Hsp27-targeted molecules interfering with its structural organization. Using the peptide aptamer (PA) strategy, we isolated PAs that specifically interact with Hsp27 and not with the other members of the small heat shock protein family. In mammalian cell cultures, PAs expression perturbed the dimerization and oligomerization of Hsp27, and acted as negative regulators of the antiapoptotic and cytoprotective activities of this protein. Further studies analyzing SQ20B cell xenografts in immunocompromised mice showed that PAs strongly reduced tumor development through cell cycle arrest. Our data suggest that PAs could provide a potential tool to develop strategies for the discovery of Hsp27 chemical inhibitors. Oncogene (2011) 30, 3672-3681; doi:10.1038/onc.2011.73;published online 21 March 2011