Department of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA.
University of Pittsburgh Cancer Institute 5117 Centre Ave., Pittsburgh, PA 15213, USA.
Mol Cancer Ther. 2013 Nov;12(11):2559-68. doi: 10.1158/1535-7163.MCT-13-0284. Epub 2013 Aug 21.
Hsp90 is widely overexpressed in cancer cells and believed to be essential for the maintenance of malignant phenotypes. Targeting Hsp90 by small molecules has shown promise in solid and hematologic malignancies, which likely involves degradation of client oncoproteins in a cell-type-specific manner. In this study, we found that structurally unrelated Hsp90 inhibitors induce DNA damage and apoptosis via p53-dependent induction of PUMA, which indirectly triggers Bax activation and mitochondrial dysfunction in colon cancer cells. Deficiency in PUMA, BAX, or p53, at lesser extent, abrogated 17-allylamino-17-demethoxygeldanamycin (17-AAG)-induced apoptosis and mitochondrial dysfunction, and enhanced clonogenic cell survival. Furthermore, suppression of p53-dependent p21 induction or enhanced p53 activation synergized with 17-AAG to induce PUMA-dependent apoptosis. Finally, PUMA was found to mediate apoptotic and therapeutic responses to the 17-AAG analog 17-DMAG in xenografts. These results show an important role of the p53/PUMA/Bax axis in Hsp90 inhibitor-induced killing of p53 wild-type cells, and have important implications for their clinical applications.
热休克蛋白 90（Hsp90）在癌细胞中广泛过表达，被认为是维持恶性表型所必需的。小分子靶向 Hsp90 在实体瘤和血液恶性肿瘤中显示出前景，这可能涉及以细胞类型特异性的方式降解客户癌蛋白。在这项研究中，我们发现结构上不相关的 Hsp90 抑制剂通过 p53 依赖性诱导 PUMA 诱导 DNA 损伤和细胞凋亡，这间接触发了结肠癌细胞中 Bax 的激活和线粒体功能障碍。在较小程度上，PUMA、BAX 或 p53 的缺乏会消除 17- 烯丙基-17-去甲氧基格尔德霉素（17-AAG）诱导的细胞凋亡和线粒体功能障碍，并增强集落形成细胞的存活。此外，抑制 p53 依赖性 p21 诱导或增强 p53 激活与 17-AAG 协同作用诱导依赖于 PUMA 的细胞凋亡。最后，发现 PUMA 介导了对 17-AAG 类似物 17-DMAG 的异种移植物中的凋亡和治疗反应。这些结果表明，p53/PUMA/Bax 轴在 Hsp90 抑制剂诱导的 p53 野生型细胞杀伤中起重要作用，这对其临床应用具有重要意义。
