Extracellular heat shock protein (Hsp)70 and Hsp90α assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion.
Extracellular heat shock protein (Hsp)70 and Hsp90α assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion.
复制标题
DOI：
10.1371/journal.pone.0018848
复制
发表时间：
2011-04-14
期刊：
影响因子：
3.7
通讯作者：
Jay DG
中科院分区：
文献类型：
--
作者：
Sims JD;McCready J;Jay DG
在女性癌症相关死亡中，乳腺癌仅次于肺癌，其中大部分死亡是由转移引起的。更好地了解迁移和侵袭（转移的两个早期步骤）对于开发抑制乳腺癌转移的治疗方法至关重要。在针对侵袭所需蛋白质的功能性蛋白质组学筛选中，鉴定出细胞外热休克蛋白 90 α (Hsp90α)，并显示其可激活基质金属蛋白酶 2 (MMP-2)。 Hsp90α 激活 MMP-2 的机制尚不清楚。细胞内 Hsp90α 通常与共伴侣复合物一起发挥作用，这导致我们假设 Hsp90α 在细胞外也具有类似的功能。在这项研究中，我们表明乳腺癌细胞外的共伴侣复合物有助于 Hsp90α 介导的 MMP-2 激活。我们证明辅助伴侣 Hsp70、Hop、Hsp40 和 p23 存在于乳腺癌细胞外部，并在体外和乳腺癌条件培养基中与 Hsp90α 共免疫沉淀。这些共伴侣还在体外增强了 Hsp90α 和 MMP-2 的关联。这种共伴侣复合物在体外增强 Hsp90α 介导的 MMP-2 激活，而在条件培养基中抑制 Hsp70 会减少这种激活并减少癌细胞迁移和侵袭。总之，这些发现支持这样一种模型：Hsp90α 介导的细胞外共伴侣复合物激活 MMP-2 会增加乳腺癌细胞的迁移和侵袭。我们的研究提供了对 MMP-2 激活的新途径的深入了解，并建议 Hsp70 作为抗转移药物开发的额外细胞外靶点。
Breast cancer is second only to lung cancer in cancer-related deaths in women, and the majority of these deaths are caused by metastases. Obtaining a better understanding of migration and invasion, two early steps in metastasis, is critical for the development of treatments that inhibit breast cancer metastasis. In a functional proteomic screen for proteins required for invasion, extracellular heat shock protein 90 alpha (Hsp90α) was identified and shown to activate matrix metalloproteinase 2 (MMP-2). The mechanism of MMP-2 activation by Hsp90α is unknown. Intracellular Hsp90α commonly functions with a complex of co-chaperones, leading to our hypothesis that Hsp90α functions similarly outside of the cell. In this study, we show that a complex of co-chaperones outside of breast cancer cells assists Hsp90α mediated activation of MMP-2. We demonstrate that the co-chaperones Hsp70, Hop, Hsp40, and p23 are present outside of breast cancer cells and co-immunoprecipitate with Hsp90α in vitro and in breast cancer conditioned media. These co-chaperones also increase the association of Hsp90α and MMP-2 in vitro. This co-chaperone complex enhances Hsp90α-mediated activation of MMP-2 in vitro, while inhibition of Hsp70 in conditioned media reduces this activation and decreases cancer cell migration and invasion. Together, these findings support a model in which MMP-2 activation by an extracellular co-chaperone complex mediated by Hsp90α increases breast cancer cell migration and invasion. Our studies provide insight into a novel pathway for MMP-2 activation and suggest Hsp70 as an additional extracellular target for anti-metastatic drug development.
登录
查看更多内容
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
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。
影响因子：
3.8
作者：
McCready J;Sims JD;Chan D;Jay DG
通讯作者：
Jay DG
影响因子：
3.8
作者：
Chen, Jing-Hsien;Lin, Hui-Hsuan;Wang, Chau-Jong
通讯作者：
Wang, Chau-Jong
影响因子：
5.3
作者：
Cheng, Chieh-Fang;Fan, Jianhua;Li, Wei
通讯作者：
Li, Wei
影响因子：
1.8
作者：
Loftus, John P.;Belknap, James K.;Black, Samuel J.
通讯作者：
Black, Samuel J.