The Neutrophil Elastase Inhibitor Elafin Triggers Rb-Mediated Growth Arrest and Caspase-Dependent Apoptosis in Breast Cancer
The Neutrophil Elastase Inhibitor Elafin Triggers Rb-Mediated Growth Arrest and Caspase-Dependent Apoptosis in Breast Cancer
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DOI：
10.1158/0008-5472.can-10-1547
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发表时间：
2010-09-15
期刊：
影响因子：
11.2
通讯作者：
Keyomarsi, Khandan
中科院分区：
文献类型：
--
作者：
Caruso, Joseph A.;Hunt, Kelly K.;Keyomarsi, Khandan
弹性蛋白是一种中性粒细胞弹性蛋白酶的内源性抑制剂，在人乳腺上皮细胞中表达，但在乳腺癌细胞中转录下调。我们假设弹力素可能在乳腺癌的背景下发挥肿瘤抑制活性。在这项研究中，我们表明，视网膜母细胞瘤（Rb）的途径管理的抗肿瘤特性的弹力素。在具有功能性Rb的乳腺癌细胞中，弹性蛋白的表达触发Rb依赖性细胞周期停滞。Elafin在缺乏Rb的乳腺癌细胞系中也表现出抑制活性，但这与诱导caspase-3依赖性、p53非依赖性凋亡细胞死亡有关。正常乳腺上皮细胞不受弹力素的影响。总的来说，这些结果表明，弹性蛋白酶介导的肿瘤抑制作用是细胞抑制或细胞毒性的Rb状态。我们的研究结果表明，弹性蛋白酶可以作为一种治疗方式来治疗乳腺癌，而不会对正常增殖细胞产生毒性。Cancer Res; 70（18）; 7125-36.（C）2010年AACR。
Elafin, an endogenous inhibitor of neutrophil elastase, is expressed in human mammary epithelial cells but is transcriptionally downregulated in breast cancer cells. We hypothesized that elafin may exert a tumor-suppressive activity in the context of breast cancer. In this study, we show that the retinoblastoma (Rb) pathway governs the antitumor properties of elafin. In breast cancer cells with functional Rb, the expression of elafin triggered Rb-dependent cell cycle arrest. Elafin also exhibited suppressive activity in breast cancer cell lines lacking Rb, but this was associated with an induction of caspase-3-dependent, p53-independent apoptotic cell death. Normal mammary epithelial cells were not affected by elafin. Collectively, these results argue that elafin mediates tumor-suppressive effects that are cytostatic or cytotoxic depending on the Rb status. Our findings suggest that elafin could be engineered as a therapeutic modality to treat breast cancer without toxicity to normal proliferating cells. Cancer Res; 70(18); 7125-36. (C)2010 AACR.