姜黄素通过抑制MMP-2 酶切TRAIL促进DcR1阳性肺腺癌凋亡

项目名称： 姜黄素通过抑制MMP-2 酶切TRAIL促进DcR1阳性肺腺癌凋亡

项目编号： No.81202953

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学八处

项目作者： 李妍

作者单位： 吉林医药学院

项目金额： 23万元

中文摘要： 转染TRAIL基因可选择性、高效地诱导肿瘤细胞凋亡,但肺腺癌严重耐药。TRAIL高效、低毒的优势吸引我们不断探索增敏策略。TRAIL与功能性受体DR4、DR5在细胞膜脂筏内组装为死亡诱导信号复合物(DISC)；而诱骗受体DcR1和DcR2通过竞争结合TRAIL阻断凋亡。表型为DR4+DR5+DcR1+ DcR2-肺腺癌A549对TRAIL高度耐受，除DcR1外，MMP-2可能通过酶切跨膜型TRAIL的脱落而降低DISC组装，从而参与耐药。在发现低浓度姜黄素上调TRAIL 跨膜分布，并增强A549对TRAIL诱导凋亡敏感性的基础上，采用流式细胞术、免疫共沉淀等技术，结合动物实验来阐明姜黄素新的药理作用："通过抑制MMP-2 酶切TRAIL而促进DcR1阳性肺腺癌凋亡"。本项目前期准备扎实、设计新颖、研究方案合理，将为应用低浓度姜黄素联合TRAIL 抗肿瘤奠定理论基础。

中文关键词： 肿瘤坏死因子相关凋亡诱导配体；肺癌；诱骗受体1；凋亡；姜黄素

英文摘要： TRAIL choosed to induce specific and strong apoptosis in tumor cells. Although some tumors，including adenocarcinoma keep resistance to TRAIL-induced apoptosis，the benefits of its safety for normal cells droved people making effect to overcome the resistance. Functional death inducing signaling complex (DISC) would be assembled in lipid raft among cell membrane following TRAIL bounding with DR4 or DR5.But the decoy receptors DcR1 and DcR2 would attenuated cell death by occupying TRAIL and blocking DISC formation. An adenocarcinoma cells,A549 (with a phenotype of DR4+DR5+DcR1+ DcR2- ) keeps strong resistance to rhTRAIL or TRAIL gene transfection. Except DcR1, shedding mTRAIL from cell membrane by MMP-2 could also be responsible for this phenomenon. We found that lower concentration of curcumin could up-regulated TRAIL loading on cell membrane and promoted apoptosis induced by TRAIL gene transfection. Based on these, membrane-bound TRAIL was determined by flow cytometry. TRAIL and its receptors localized in lipid rafts would be analyzed by immunoprecipitation and laser scanning confocalmicroscope.The efficacy of curcumin to improve TRAIL-induced apoptosis and tumor extinction could also be investigated in animal experiment.The proposal has a solid preliminary studies,innovative ideas and reasonable design and metho

英文关键词： TRAIL；lung cancer；decoy receptor 1；apoptosis；curcumin