UVRAG介导的自噬在二烯丙基二硫诱导白血病细胞K562凋亡中的作用及分子机制

Anti-tumor drugs kill tumor cells mainly via inducing apoptosis. Recent studies have shown that autophagy involved in the regulation of tumor occurrence and development. however, the relationship and molecular mechanism between autophagy and apoptosis remain not elucidated. In previous studies, we had provided evidence that diallyl disulfide induced apoptosis in K562 cells in time and dose dependent manner, and autophagy function associated gene,ultraviolet irradiation resistance-associated gene(UVRAG),had a role in the process of regulating apoptosis by interfering the translocation of BAX to mitochondria which was published in EMBO Reports. However, whether autophagy induced by UVRAG related to apoptosis induced by DADS remains unknown. Based on this, we will firstly detected whether DADS could induce autophagy in K562 cells, then we will investigate the role and molecular mechanism of UVRAG in both apoptosis and autophagy. The results of this research will offer new insights in the cross talk between apoptosis and autophagy and provide effective methods and targets for the therapy of leukemia, ultimately provide evidences for applying DADS to clinic therapy.

抗肿瘤药物主要是通过诱导肿瘤细胞凋亡来发挥杀死肿瘤细胞的作用。最新研究表明，自噬参与调控肿瘤的发生、发展过程，然而细胞自噬与凋亡的相互关系及其分子机制尚未阐明。本课题组前期研究表明二烯丙基二硫 (DADS)可呈时间和剂量依赖性的方式诱导白血病细胞K562凋亡，而自噬功能相关基因-抗紫外线相关基因（UVRAG）可通过干扰Bcl2相关蛋白X的线粒体转位而抑制凋亡的发生，相关工作已发表在EMBO Reports杂志上。然而UVRAG介导的细胞自噬与DADS诱导肿瘤细胞凋亡之间是否存在关系尚未见报道。基于此，本项目首先检测DADS是否能够诱导白血病细胞K562发生自噬，然后再探讨UVRAG对DADS诱导凋亡及自噬过程中的影响及其分子机制，为探求凋亡和自噬之间的相互关系提供新的线索，并为白血病的防治提供有效的策略和靶标，最终为DADS应用于临床奠定分子基础。

为探讨和鉴定自噬基因UVRAG、Beclin1在二烯丙基二硫诱导白血病细胞K562凋亡的表达和分子机制。.本项目通过一系列研究方法，确定了二烯丙基二硫能够诱导白血病细胞K562发生自噬性死亡，探讨了凋亡相关基因Caspase3，自噬相关基因UVRAG、Beclin1在二烯丙基二硫诱导凋亡及自噬过程中的作用机制；通过改变UVRAG的表达，进一步阐明了Caspase3，LC3，P62等基因在白血病细胞K562中的分子机制；证明了UVRAG在二烯丙基二硫诱导下具有介导白血病细胞分泌Caspase3，LC3，P62的作用；初步探讨了UVRAG介导的自噬在DADS诱导K562细胞凋亡中的关系,为阐明凋亡和自噬之间的相互关系提供了部分依据。在基金的支持下较圆满的完成了课题计划，初步探讨了DADS应用于临床的部分分子基础。