Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation.
Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation.
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细胞外Hsp90alpha通过外泌体的分泌增加了癌细胞的运动：纤溶酶原活化的作用。
DOI：
10.1186/1471-2407-10-294
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发表时间：
2010-06-16
期刊：
影响因子：
3.8
通讯作者：
Jay DG
中科院分区：
文献类型：
--
作者：
McCready J;Sims JD;Chan D;Jay DG
转移是一个多步骤的过程，是癌症患者死亡的主要原因。目前的治疗在靶向转移方面无效。分子伴侣hsp 90 α由侵袭性癌细胞分泌并激活MMP-2以增强侵袭性，这是转移的第一步所需的。我们分析了在存在或不存在hsp 90 α的情况下用外源性外泌体处理的侵袭性癌细胞的形态和运动性。我们通过质谱和免疫沉淀鉴定纤溶酶原作为细胞外热休克蛋白90 α的潜在客户蛋白。进行纤溶酶激活试验和迁移试验以测试纤溶酶原是否被细胞外hsp 90 α激活并在迁移中起作用。我们发现hsp 90 α在侵袭性癌细胞的外泌体中分泌，并有助于其侵袭性。我们鉴定了热休克蛋白90 α和组织纤溶酶原激活剂之间的一种新的相互作用，这种相互作用与也存在于外泌体中的膜联蛋白II一起激活纤溶酶。细胞外热休克蛋白90 α促进纤溶酶活化以及增加纤溶酶依赖的细胞运动性。我们的数据表明，hsp 90 α是由侵袭性癌细胞通过外泌体释放的，并涉及hsp 90 α激活纤溶酶，纤溶酶是癌细胞侵袭中起作用的第二种蛋白酶。
Metastasis is a multi-step process that is responsible for the majority of deaths in cancer patients. Current treatments are not effective in targeting metastasis. The molecular chaperone hsp90α is secreted from invasive cancer cells and activates MMP-2 to enhance invasiveness, required for the first step in metastasis. We analyzed the morphology and motility of invasive cancer cells that were treated with exogenous exosomes in the presence or absence of hsp90α. We performed mass spectrometry and immunoprecipitation to identify plasminogen as a potential client protein of extracellular hsp90α. Plasmin activation assays and migration assays were performed to test if plasminogen is activated by extracellular hsp90α and has a role in migration. We found that hsp90α is secreted in exosomes in invasive cancer cells and it contributes to their invasive nature. We identified a novel interaction between hsp90α and tissue plasminogen activator that together with annexin II, also found in exosomes, activates plasmin. Extracellular hsp90α promotes plasmin activation as well as increases plasmin dependent cell motility. Our data indicate that hsp90α is released by invasive cancer cells via exosomes and implicates hsp90α in activating plasmin, a second protease that acts in cancer cell invasion.
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