Tanimura Susumu, Hirano A-i, Hashizume Junya, Yasunaga Masahiro, Kawabata Takumi, Ozaki Kei-ichi, Kohno Michiaki
Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
J Biol Chem. 2007 Dec 7;282(49):35430-9. doi: 10.1074/jbc.M707547200. Epub 2007 Sep 12.
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 than Hsp70 in all normal and tumor cell types examined. Tumor cells with a high HspBP1/Hsp70 molar ratio were more susceptible to anticancer drugs than were those with a low ratio. Ectopic expression of HspBP1 enhanced this effect of anticancer drugs in a manner 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 up-regulated HspBP1 expression, whereas prevention of such up-regulation by RNA interference reduced the susceptibility of tumor cells to anticancer drugs. Overexpression of HspBP1 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.
70 kDa热休克蛋白（Hsp70）在多种肿瘤细胞类型中上调，并有助于这些细胞对抗癌药物诱导的细胞死亡产生抗性。Hsp70结合蛋白1（HspBP1）调节Hsp70的活性，但其生物学意义尚不清楚。我们现在研究了HspBP1是否可能干扰Hsp70的促生存功能，Hsp70的促生存功能至少部分是通过抑制溶酶体膜与死亡相关的通透性来介导的。在所有检测的正常和肿瘤细胞类型中，发现HspBP1的表达水平高于Hsp70。HspBP1/Hsp70摩尔比高的肿瘤细胞比摩尔比低的肿瘤细胞对抗癌药物更敏感。HspBP1的异位表达以一种既依赖于HspBP1与Hsp70结合的能力又对轻度热休克诱导的Hsp70敏感的方式增强了抗癌药物的这种作用。此外，抗癌药物上调HspBP1表达，而通过RNA干扰阻止这种上调会降低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、组织蛋白酶从溶酶体释放到细胞质中以及抗癌药物诱导的caspase-3激活。这些结果表明，HspBP1通过拮抗Hsp70的促生存活性，使肿瘤细胞对组织蛋白酶介导的细胞死亡敏感。
