Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway.
Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway.
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新型 smac 模拟物 APG-1387 通过 TNF-α、核糖体和自噬介导的细胞死亡途径引发卵巢癌细胞杀伤
DOI：
10.1186/s13046-018-0703-9
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发表时间：
2018-03-12
期刊：
影响因子：
--
通讯作者：
Yang DJ
中科院分区：
文献类型：
--
作者：
Li BX;Wang HB;Qiu MZ;Luo QY;Yi HJ;Yan XL;Pan WT;Yuan LP;Zhang YX;Xu JH;Zhang L;Yang DJ
背景卵巢癌是一种致死性疾病。凋亡抑制蛋白（IAP）是细胞凋亡的关键调节因子，在卵巢癌中经常失调。IAP蛋白的过表达与肿瘤的发生、治疗抵抗和不良预后相关。重新安装功能性细胞死亡机制的IAP蛋白的药理学抑制可能是一个有吸引力的治疗策略，为治疗卵巢cancer.MethodsCCK-8和集落形成试验进行检查细胞毒活性。采用荧光显微镜、流式细胞仪和TUNEL法检测细胞凋亡。 ELISA法检测TNFα蛋白。半胱天冬酶活性测定用于半胱天冬酶活化评价。进行免疫沉淀和siRNA干扰以进行功能分析。Western blotting分析蛋白表达。结果APG-1387对卵巢癌细胞的生长和克隆形成细胞的存活有较强的抑制作用。APG-1387通过下调IAP蛋白和诱导caspase-8/FADD/RIP 1复合物，进而驱动caspase-8激活，诱导RIP 1和TNFα依赖的卵巢癌细胞凋亡。APG-1387处理后，NF-κB信号通路被激活，RIP 1参与NF-κB的激活。APG-1387诱导细胞保护性自噬，同时触发卵巢癌细胞凋亡，抑制自噬增强APG-1387诱导的细胞凋亡。结论APG-1387可靶向IAP蛋白诱导卵巢癌细胞凋亡，为进一步研究APG-1387在卵巢癌中的作用机制提供了理论依据。
BackgroundOvarian cancer is a deadly disease. Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. Overexpression of IAPs proteins has been correlated with tumorigenesis, treatment resistance and poor prognosis. Reinstalling functional cell death machinery by pharmacological inhibition of IAPs proteins may represent an attractive therapeutic strategy for treatment of ovarian cancer.MethodsCCK-8 and colony formation assay was performed to examine cytotoxic activity. Apoptosis was analyzed by fluorescence microscopy, flow cytometry and TUNEL assay. Elisa assay was used to determine TNFα protein. Caspase activity assay was used for caspase activation evaluation. Immunoprecipitation and siRNA interference were carried out for functional analysis. Western blotting analysis were carried out to test protein expression. Ovarian cancer cell xenograft nude mice model was used for in vivo efficacy evaluation.ResultsAPG-1387 demonstrated potent inhibitory effect on ovarian cancer cell growth and clonogenic cell survival. APG-1387 induced RIP1- and TNFα-dependent apoptotic cell death in ovarian cancer through downregulation of IAPs proteins and induction of caspase-8/FADD/RIP1 complex, which drives caspase-8 activation. NF-κB signaling pathway was activated upon APG-1387 treatment and RIP1 contributed to NF-κB activation. APG-1387 induced cytoprotective autophagy while triggering apoptosis in ovarian cancer cells and inhibition of autophagy enhanced APG-1387-induced apoptotic cell death. APG-1387 exhibited potent antitumor activity against established human ovarian cancer xenografts.ConclusionsOur results demonstrate that APG-1387 targets IAPs proteins to potently elicit apoptotic cell death in vitro and in vivo, and provide mechanistic and applicable rationale for future clinical evaluation of APG-1387 in ovarian cancer.
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DOI：
10.1042/bj20100814
发表时间：
2010-09-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Altieri DC
通讯作者：
Altieri DC
DOI：
10.12659/msm.895562
发表时间：
2015-10-19
期刊：
Medical science monitor : international medical journal of experimental and clinical research
影响因子：
--
作者：
Liu X;Ma L;Rao Q;Mao Y;Xin Y;Xu H;Li C;Wang X
通讯作者：
Wang X
影响因子：
10.5
作者：
Lin, Y;Devin, A;Liu, ZG
通讯作者：
Liu, ZG
影响因子：
13.3
作者：
Furuya, Norihiko;Yu, Jie;Levine, Beth
通讯作者：
Levine, Beth
影响因子：
16
作者：
Bertrand, Mathieu J. M.;Milutinovic, Snezana;Barker, Philip A.
通讯作者：
Barker, Philip A.