Isowalsuranolide（HXJ-2351）诱导溶酶体生成及细胞凋亡的分子机制研究

	Isowalsuranolide（HXJ-2351）诱导溶酶体生成及细胞凋亡的分子机制研究; Molecular Mechanisms of Isowalsuranolide (HXJ-2351) Induced Lysosomal Biogenesis and Apoptosis
	陈远志
导师	郝小江
摘要	Tumors are among the deadliest diseases that seriously endanger the lives and health of people globally. Chemotherapy is still the one of the basis of tumor treatment. Many chemotherapeutic agents used clinically are derived from plant extracts and their derivatives. It is an effective method to develop new antitumor drugs by screening in vitro cytotoxic activity to identify compounds with antitumor activities and to study the mechanisms of those antitumor activities. Isowalsuranolide (HXJ-2351) is a tetranortriterpenoid that is extracted and isolated from the Walsura robusta Roxb. Hort. It is a limonoid compound and can induce a wide range of biological activities. Many studies have shown that limonin compounds exhibited cytotoxicity towards tumor cells, but the mechanisms of actions are unclear. Therefore, it is worthwhile to study the cytotoxicity of limonin compounds in tumor cells and how do limonin compounds, especially Isowalsuranolide, exert its antitumor activity. Apoptosis refers to the autonomous and orderly death of cells controlled by a series of genes in order to maintain internal environment homoestasis. Apoptosis is different from cell necrosis. It involves the activation, expression and regulation of a series of genes. It is not a kind of autologous injury under pathological conditions, but a process of death actively striving for better adaptation to the living environment. In the second chapter of this thesis, we found that HXJ-2351 could induce apoptosis of tumor cells. At the same time, HXJ-2351 could induce the accumulation of endogenous ROS and endoplasmic reticulum stress (ER stress). The ER stress and apoptosis induced by HXJ-2351 depended on the accumulation of endogenous ROS. After futher investigation, we found that HXJ-2351 induced apoptosis was through the ROS-ER Stress-CHOP-Bim-caspase pathway. This study provided evidence of how HXJ-2351 induced apoptosis. Autophagy is a highly conserved lysosomal degradation process in cells, which can degrade unnecessary or malfunctioning organelles and biological macromolecules, thereby playing a key regulatory role in cell survival and normal function maintenance. As an integral part of the autophagy process, lysosomes play a vital role in the process of autophagy. In chapter 3 of this thesis, we found that HXJ-2351 could induce lysosomal biogenesis as well as the protective autophagic flux, by using western blot, immunofluorescence staining and other related methods. The HXJ-2351 induced transactivation of genes related to autophagy and lysosome biogenesis was dependent on TFEB and TFE3. We found that HXJ-2351 could induce nuclear translocation of endogenous and exogenous TFEB and TFE3. At the same time, we found that HXJ-2351 activated TFEB / TFE3 is dependent on Calcineurin and mTORC1.
	2020-05
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/74115
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	陈远志. Isowalsuranolide（HXJ-2351）诱导溶酶体生成及细胞凋亡的分子机制研究, Molecular Mechanisms of Isowalsuranolide (HXJ-2351) Induced Lysosomal Biogenesis and Apoptosis[D],2020.

条目包含的文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
陈远志-陈远志国科大93b00e32-e（4328KB）	学位论文		限制开放	CC BY-NC-SA	请求全文