A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells
A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells
复制标题
DOI：
10.1038/sj.onc.1208888
复制
发表时间：
2005-11-01
期刊：
影响因子：
8
通讯作者：
Sun, Y
中科院分区：
文献类型：
--
作者：
Bockbrader, KM;Tan, MJ;Sun, Y
凋亡蛋白抑制剂 (IAP) 通过其杆状病毒 IAP 重复 (BIR) 结构域结合并抑制活性 caspase-3、-7 和 -9，从而抑制细胞凋亡。在细胞凋亡过程中，IAP 对 caspase 的抑制作用可以通过线粒体蛋白第二种线粒体衍生的 caspase 激活剂 (Smac) 进行负调节。 Smac 与多种 IAP 发生物理相互作用，并减轻它们对 caspase-3、-7 和 -9 的抑制作用。最近，一种小分子 Smac 模拟化合物 (Smac-mimic) 被鉴定和表征，该化合物可增强 TNF 相关凋亡诱导配体 (TRAIL) 和肿瘤坏死因子 (TNF)-α 介导的胶质母细胞瘤 T98G 细胞和 HeLa 细胞的细胞死亡。为了确定该化合物在乳腺癌细胞中的功效，我们首先测量了九种独立乳腺癌细胞系中三种 IAP 的蛋白表达：XIAP、cIAP-1 和 cIAP-2。选择了三种细胞系：高IAP表达系MDAMB231和两种低IAP表达系T47D和MDA-MB-453。测试细胞系对单独的Smac-mimic或与TRAIL或依托泊苷组合的敏感性。单独作用时，Smac-mimic 在表达高 IAP 的 MDA-MB-231 细胞中非常有效，细胞毒性 IC50 为 3.8 nM，但在表达低 IAP 的 T47D 和 MDA-MB-453 细胞中以高得多的浓度失活。事实上，单独低至 2.5 nM 的 Smac-mimic 就足以激活 caspase-3 并诱导 MDA-MB-231 细胞凋亡。在与 TRAIL 或依托泊苷联合治疗中，Smac-mimic 使 MDA-MB-231 细胞中的细胞对生长抑制显着敏感，但在 T47D 和 MDA-MB-453 细胞中的程度较小。此外，它显着协同 MDA-MB-231，但不协同 T47D 细胞抵抗 TRAIL 或依托泊苷诱导的细胞凋亡。因此，在这些细胞系中，Smac-mimic 以明显的 IAP 依赖性方式发挥作用，单独诱导细胞凋亡，并通过 caspase-3 激活使乳腺癌细胞对 TRAIL 或依托泊苷诱导的细胞凋亡敏感。
Inhibitor of apoptosis protein (IAP) suppresses apoptosis through binding and inhibiting active caspases-3,-7 and -9 via its baculoviral IAP repeat (BIR) domains. During apoptosis the caspase inhibition by IAPs can be negatively regulated by a mitochondrial protein second mitochondrial-derived activator of caspase (Smac). Smac physically interacts with multiple IAPs and relieves their inhibitory effect on caspases-3,-7 and -9. Recently, a small molecule Smac-mimic compound (Smac-mimic), which potentiates TNF-related apoptosis-inducing ligand (TRAIL) and tumor necrosis factor (TNF)-alpha mediated cell death in glioblastoma T98G cells and HeLa cells, was identified and characterized. To determine the efficacy of this compound in breast cancer cells, we first measured protein expression of three IAPs: XIAP, cIAP-1, and cIAP-2 in nine independent breast cancer cell lines. Three cell lines were chosen: a high IAPs expressing line MDAMB231, and two low IAPs expressing lines, T47D and MDA-MB-453. The cell lines were tested for their sensitivity to Smac-mimic alone or in combination with TRAIL or etoposide. Acting alone, Smac-mimic was quite potent with a cytotoxic IC50 of 3.8 nM in high IAPs expressing MDA-MB-231 cells, but was inactive at a much higher concentration in low IAPs expressing T47D and MDA-MB-453 cells. In fact, as low as 2.5 nM of Smac-mimic alone was sufficient to activate caspase-3 and induce apoptosis in MDA-MB-231 cells. In combinational treatments with TRAIL or etoposide, Smac-mimic significantly sensitized cells to growth suppression in MDA-MB-231 cells, but to a lesser extent in T47D and MDA-MB-453 cells. Furthermore, it significantly synergized MDA-MB-231, but not T47D cells to apoptosis induced by either TRAIL or etoposide. Thus, in these cell lines, Smac-mimic acts in an apparent IAPs dependent manner to induce apoptosis alone as well as sensitizes breast cancer cells to TRAIL or etoposide induced apoptosis via caspase-3 activation.