可控活化的Caspase-3/7的非凋亡功能在乳腺肿瘤发生及发展过程中的作用

项目名称： 可控活化的Caspase-3/7的非凋亡功能在乳腺肿瘤发生及发展过程中的作用

项目编号： No.81472472

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王欣

作者单位： 天津医科大学

项目金额： 55万元

中文摘要： 绝大多数肿瘤通过抑制Caspase的上游信号途径而不是通过直接灭活凋亡途径中的Caspase来避免凋亡的，说明这些Caspase可能在肿瘤的发生发展过程中起了重要作用。我们开发了可在细胞中实时监测Caspase活性的分子工具，并在乳腺肿瘤细胞中进行筛选，发现Caspase-3/7存在有限的活化，且它们对乳腺肿瘤细胞的生长是必须的。Caspase-3/7是凋亡途径中最主要的下游效应因子，通常通过级联放大激活导致凋亡。我们的结果显示乳腺肿瘤细胞中Caspase-3/7的活化受严格控制，以致它们的有限活化并不诱导凋亡，但对生长却至关重要。因此，了解乳腺肿瘤细胞控制Caspase-3/7的有限活化的机制及其在乳腺肿瘤发生及发展过程中的作用，有助于了解乳腺肿瘤的发病机制及找出特异治疗靶点，抑制这些靶点或特异杀死乳腺肿瘤，或提高它们对已有临床药物的敏感性。此外，这种机制及相关靶点可能还有一定的广谱性。

中文关键词： C21_乳腺肿瘤；凋亡；蛋白水解酶；可控活化；级联放大

英文摘要： Cancer cells differ from normal cells in that they can immortally grow by escaping apoptosis. However, most of cancer cells acquire apoptosis-resistance ability by inactivating up-stream signals that trigger caspases cascades not by directly removing caspases, suggesting that caspases might be vital to carcinogenesis. We developed biosensors that can measure in real time caspases' activity in live cells and applied them in breast cancer cells to screen basally activated caspases. We indentified a low level of activated caspase-3/7 that were indispensable to the growth of breast cancer cells, supported by our further results obtained with shRNA and chemical compounds against caspase-3/7. Caspase-3/7 are the principal executioners in the apoptotic pathways, and they usually undergo cascade amplification. Our results showed that caspase-3/7 activity was controllably activated in breast cancer cells to avoid apoptosis but contribute to growth. Therefore, dissecting the mechanisms underlying how breast cancer cells conduct controllable activation of caspase-3/7 and figuring out the non-apoptotic role of controllably activated caspase-3/7 in the initiation and progress of breast cancer cells would be helpful to understand breast carcinogenesis as well as to find out the specific anti-breast cancer targets. The inhibition of these targets should either specifically kill breast cancer cells or sensitize them to clinical chemotherapeutical drugs. Moreover, in view of the generality of apoptosis-associated caspases in cancer cells, these findings may not be limited to breast cancer, and these anti-cancer targets most likely apply to other cancers.

英文关键词： Breast cancer;Apoptosis;Caspase;Controllable activation;Cascade amplification