凋亡因子（TRAIL）对癌细胞凋亡的机制研究

凋亡因子TRAIL（Tumor necrosis factor related apoptosis inducing ligand）能诱导肿瘤和转化细胞凋亡而不伤害正常细胞.TRAIL与细胞膜上死亡受体（death receptors,DR）结合,引发受体蛋白构象变化,经胞膜内受体死亡域（death domain,DD）募集接头蛋白FADD（Fas associateddeath domain）,再经过FADD的死亡效应域（death effector domain,DED）与凋亡蛋白解酶原-8/10（procaspase-8/10）的DED相互结合,形成DISC（death-inducing signaling complex）,引起凋亡蛋白解酶（caspase）级联反应,促使癌细胞凋亡.目前,可溶性重组人性化TRAIL（rhTRAIL）和抗DR4/5单克隆抗体已进入临床Ⅰ/Ⅱ期实验阶段.但绝大部分癌细胞对TRAIL有耐受或引起耐受,耐受机制主要是由于IAP（Inhibitor of Apoptosis Protein）,Bcl-2（B-cell lymphoma-2）及cFLIP（cellular FLICE/caspase 8-like inhibitory protein,胞质凋亡抑制蛋白）家族蛋白的过表达而产生.因此,为了克服TRAIL的耐受,已有多种小分子IAP和Bcl-2拮抗剂在研发并进行临床实验.至今尚无cFLIP拮抗剂的报导.

Study on TRAIL Receptor-Mediated Apoptosis of Cancer Cells

TRAIL（Tumor necrosis factor related apoptosis inducing ligand） can induce apoptosis of broad spectrum of tumors and transformed cells,while sparing most normal cells.TRAIL binds to its death receptors（DR） to trigger a conformational change of receptor proteins.The death domain（DD） of the DR inside of the cell plasma membrane recruits FADD（Fas associated death domain） via the interaction of DD.Subsequently,DISC（death-inducing signaling complex） is formed through the DED：DED interaction between FADD and procaspase-8/10.Finally,apoptosis is induced through a cascade of caspase activation.The recombinatory human TRAIL and monoclonal antibodies of DR are currently under clinical phase I/II trials.However,a large number of cancers are resistant to TRAIL.The mechanisms of TRAIL resistance in tumor cells are mainly due to the over expression of IAP（Inhibitor of Apoptosis Protein）,cFLIP（cellular FLICE/caspase-8-like inhibitory protein） and Bcl-2（B-cell lymphoma-2） family proteins.Therefore,several small molecule antagonists for resistant proteins of IAP and Bcl-2,but not yet of cFLIP,have been discovered and currently under clinical trials to overcome the resistance.