Kamal Adeela, Thao Lia, Sensintaffar John, Zhang Lin, Boehm Marcus F, Fritz Lawrence C, Burrows Francis J
Conforma Therapeutics Corporation, 9393 Towne Centre Drive, Suite 240, San Diego, California 92121, USA.
Nature. 2003 Sep 25;425(6956):407-10. doi: 10.1038/nature01913.
Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signalling proteins, including HER-2/ErbB2, Akt, Raf-1, Bcr-Abl and mutated p53. Hsp90 inhibitors bind to Hsp90, and induce the proteasomal degradation of Hsp90 client proteins. Although Hsp90 is highly expressed in most cells, Hsp90 inhibitors selectively kill cancer cells compared to normal cells, and the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) is currently in phase I clinical trials. However, the molecular basis of the tumour selectivity of Hsp90 inhibitors is unknown. Here we report that Hsp90 derived from tumour cells has a 100-fold higher binding affinity for 17-AAG than does Hsp90 from normal cells. Tumour Hsp90 is present entirely in multi-chaperone complexes with high ATPase activity, whereas Hsp90 from normal tissues is in a latent, uncomplexed state. In vitro reconstitution of chaperone complexes with Hsp90 resulted in increased binding affinity to 17-AAG, and increased ATPase activity. These results suggest that tumour cells contain Hsp90 complexes in an activated, high-affinity conformation that facilitates malignant progression, and that may represent a unique target for cancer therapeutics.
热休克蛋白90（Hsp90）是一种分子伴侣，在致癌信号蛋白的构象成熟过程中发挥关键作用，这些蛋白包括HER-2/ErbB2、Akt、Raf-1、Bcr-Abl和突变型p53。Hsp90抑制剂与Hsp90结合，并诱导Hsp90客户蛋白的蛋白酶体降解。尽管Hsp90在大多数细胞中高度表达，但与正常细胞相比，Hsp90抑制剂能选择性地杀死癌细胞，目前Hsp90抑制剂17-烯丙基氨基格尔德霉素（17-AAG）正处于I期临床试验阶段。然而，Hsp90抑制剂肿瘤选择性的分子基础尚不清楚。在此我们报告，肿瘤细胞来源的Hsp90对17-AAG的结合亲和力比正常细胞来源的Hsp90高100倍。肿瘤Hsp90完全存在于具有高ATP酶活性的多分子伴侣复合物中，而正常组织中的Hsp90处于潜在的、未复合的状态。用Hsp90进行分子伴侣复合物的体外重组导致对17-AAG的结合亲和力增加以及ATP酶活性增强。这些结果表明，肿瘤细胞含有处于激活的、高亲和力构象的Hsp90复合物，这种构象促进恶性进展，并且可能代表癌症治疗的一个独特靶点。
