Breast Cancer MDA-MB-231 Cells Use Secreted Heat Shock Protein-90alpha (Hsp90α) to Survive a Hostile Hypoxic Environment.
Breast Cancer MDA-MB-231 Cells Use Secreted Heat Shock Protein-90alpha (Hsp90α) to Survive a Hostile Hypoxic Environment.
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DOI：
10.1038/srep20605
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发表时间：
2016-02-05
影响因子：
4.6
通讯作者：
Li W
中科院分区：
文献类型：
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作者：
Dong H;Zou M;Bhatia A;Jayaprakash P;Hofman F;Ying Q;Chen M;Woodley DT;Li W
体内快速生长的肿瘤往往生长超出其周围可用的血液供应，使其自身处于严重缺氧的微环境中。了解肿瘤细胞如何适应缺氧，可能有助于开发新的肿瘤治疗方法。考虑到扩大的肿瘤的血液灌注有限，使肿瘤细胞存活的任何因素都可能来自肿瘤细胞本身或其相关的基质细胞。在本报告中，我们发现过表达hif -1α-的乳腺癌细胞MDA-MB-231分泌热休克蛋白90α (Hsp90α)并利用它在缺氧下存活。缺氧导致肿瘤细胞分泌Hsp90α的缺失，有利于细胞毒性的发生，而在敲除Hsp90α的肿瘤细胞中补充重组Hsp90α蛋白，而不是Hsp90β蛋白，通过LDL受体相关蛋白-1 （LRP1）受体的自分泌机制防止缺氧诱导的细胞死亡。最后，用单克隆抗体1G6-D7直接抑制分泌的Hsp90α，可增强肿瘤细胞在缺氧下的死亡。因此，分泌的Hsp90α是缺氧条件下某些肿瘤的新生存因子。
Rapidly growing tumours in vivo often outgrow their surrounding available blood supply, subjecting themselves to a severely hypoxic microenvironment. Understanding how tumour cells adapt themselves to survive hypoxia may help to develop new treatments of the tumours. Given the limited blood perfusion to the enlarging tumour, whatever factor(s) that allows the tumour cells to survive likely comes from the tumour cells themselves or its associated stromal cells. In this report, we show that HIF-1α-overexpressing breast cancer cells, MDA-MB-231, secrete heat shock protein-90alpha (Hsp90α) and use it to survive under hypoxia. Depletion of Hsp90α secretion from the tumour cells was permissive to cytotoxicity by hypoxia, whereas supplementation of Hsp90α-knockout tumour cells with recombinant Hsp90α, but not Hsp90β, protein prevented hypoxia-induced cell death via an autocrine mechanism through the LDL receptor-related protein-1 (LRP1) receptor. Finally, direct inhibition of the secreted Hsp90α with monoclonal antibody, 1G6-D7, enhanced tumour cell death under hypoxia. Therefore, secreted Hsp90α is a novel survival factor for certain tumours under hypoxia.