Anticancer Drugs Upregulate HspBP 1 and Thereby Antagonize the Prosurvival Function of Hsp 70 in Tumor Cells *
Anticancer Drugs Upregulate HspBP 1 and Thereby Antagonize the Prosurvival Function of Hsp 70 in Tumor Cells *
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抗癌药物上调 HspBP 1，从而拮抗肿瘤细胞中 Hsp 70 的促生存功能*
DOI：
10.2169/internalmedicine.43.802
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发表时间：
2007
影响因子：
1.2
通讯作者：
M. Kohno
中科院分区：
文献类型：
--
作者：
A;Junya Hashizume;M. Yasunaga;T. Kawabata;Kei‐ichi Ozaki;M. Kohno
70 kDa热休克蛋白(Hsp70)在多种类型的肿瘤细胞中表达上调，并有助于这些细胞抵抗抗癌药物诱导的细胞死亡。热休克蛋白70结合蛋白1(HspBP1)调节HSP70的活性，但其生物学意义尚不清楚。我们现在已经研究了HspBP1是否可能干扰Hsp70的生存功能，这至少部分是通过抑制溶酶体膜的死亡相关通透性来介导的。HspBP1在所有正常和肿瘤细胞类型中的表达水平均高于Hsp70。HspBP1/Hsp70摩尔比高的肿瘤细胞比低摩尔比的肿瘤细胞对抗癌药物更敏感。HspBP1的异位表达增强了抗癌药物的这种作用，这种作用既依赖于HspBP1与Hsp70结合的能力，也依赖于对轻度热休克诱导Hsp70的敏感性。此外，抗癌药物上调HspBP1的表达，而通过RNA干扰抑制这种上调降低了肿瘤细胞对抗癌药物的敏感性。HspBP1的过表达促进了溶酶体膜的通透性，组织蛋白从溶酶体释放到胞浆中，以及抗癌药物诱导的caspase-3的激活。这些结果表明，HspBP1通过拮抗Hsp70的生存活性，使肿瘤细胞对组织蛋白酶介导的细胞死亡敏感。
The 70-kDa heat shock protein (Hsp70) is up-regulated in a wide variety of tumor cell types and contributes to the resistance of these cells to the induction of cell death by anticancer drugs. Hsp70 binding protein 1 (HspBP1) modulates the activity of Hsp70 but its biological significance has remained unclear. We have now examined whether HspBP1 might interfere with the prosurvival function of Hsp70, which is mediated, at least in part, by inhibition of the death-associated permeabilization of lysosomal membranes. HspBP1 was found to be expressed at a higher level thanHsp70 in all normal and tumor cell types examined. Tumor cells with a high HspBP1/Hsp70 molar ratio were more susceptible to anticancer drugs thanwere those with a low ratio. Ectopic expression ofHspBP1 enhanced this effect of anticancer drugs in amanner that was both dependent on the ability of HspBP1 to bind to Hsp70 and sensitive to the induction of Hsp70 by mild heat shock. Furthermore, anticancer drugs upregulated HspBP1 expression, whereas prevention of such upregulation by RNA interference reduced the susceptibility of tumor cells to anticancer drugs.Overexpression ofHspBP1 promoted the permeabilization of lysosomal membranes, the release of cathepsins from lysosomes into the cytosol, and the activation of caspase-3 induced by anticancer drugs. These results suggest that HspBP1, by antagonizing the prosurvival activity of Hsp70, sensitizes tumor cells to cathepsin-mediated cell death.