Our previous study showed that TP53-induced glycolysis and apoptosis regulator (TIGAR) regulated ROS, autophagy, and apoptosis in response to hypoxia and chemotherapeutic drugs. Aescin, a triterpene saponin, exerts anticancer effects and increases ROS levels. The ROS is a key upstream signaling to activate autophagy. Whether there is a crosstalk between TIGAR and aescin in regulating ROS, autophagy, and apoptosis is unknown. In this study, we found that aescin inhibited cell viability and colony formation, and induced DNA damage, cell cycle arrest, and apoptosis in cancer cell lines HCT-116 and HCT-8 cells. Concurrently, aescin increased the expression of TIGAR, ROS levels, and autophagy activation. Knockdown of TIGAR enhanced the anticancer effects of aescin in vitro and in vivo, whereas overexpression of TIGAR or replenishing TIGAR downstream products, NADPH and ribose, attenuated aescin-induced apoptosis. Furthermore, aescin-induced ROS elevation and autophagy activation were further strengthened by TIGAR knockdown in HCT-116 cells. However, autophagy inhibition by knockdown of autophagy-related gene ATG5 or 3-methyladenine (3-MA) exaggerated aescin-induced apoptosis when TIGAR was knocked down. In conclusion, TIGAR plays a dual role in determining cancer cell fate via inhibiting both apoptosis and autophagy in response to aescin, which indicated that inhibition of TIGAR and/or autophagy may be a junctional therapeutic target in treatment of cancers with aescin.

中文翻译：

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TIGAR组合通过调节大肠癌细胞中的自噬和凋亡增强了七叶皂甙的抗癌作用。

我们以前的研究表明，TP53诱导的糖酵解和凋亡调节剂（TIGAR）调节ROS，自噬和细胞凋亡，以应对缺氧和化疗药物的反应。三萜皂苷七叶皂甙具有抗癌作用，并能提高ROS水平。ROS是激活自噬的关键上游信号。TIGAR和七叶皂苷之间是否在调节ROS，自噬和细胞凋亡方面存在串扰尚不清楚。在这项研究中，我们发现七叶皂甙抑制癌细胞系HCT-116和HCT-8细胞的细胞活力和集落形成，并诱导DNA损伤，细胞周期停滞和凋亡。同时，七叶皂甙增加了TIGAR的表达，ROS水平和自噬激活。剔除TIGAR可以增强七叶皂苷在体外和体内的抗癌作用，而过表达TIGAR或补充TIGAR下游产物NADPH和核糖可减轻七叶皂苷诱导的细胞凋亡。此外，通过TIGAR敲低HCT-116细胞，进一步增强了七叶皂苷诱导的ROS升高和自噬激活。但是，敲低自噬相关基因ATG5或3-甲基腺嘌呤（3-MA）的自噬抑制作用会在TIGAR被敲低时夸大了七叶皂苷诱导的细胞凋亡。总之，TIGAR通过抑制细胞凋亡和自噬响应七叶树素​​而在决定癌细胞命运方面起着双重作用，这表明TIGAR和/或自噬的抑制作用可能是七叶树素治疗癌症的联合治疗靶点。TIGAR敲低HCT-116细胞进一步增强了七叶皂苷诱导的ROS升高和自噬激活。但是，敲低自噬相关基因ATG5或3-甲基腺嘌呤（3-MA）的自噬抑制作用会在TIGAR被敲低时夸大了七叶皂苷诱导的细胞凋亡。总之，TIGAR通过抑制细胞凋亡和自噬响应七叶树素​​而在决定癌细胞命运方面起着双重作用，这表明TIGAR和/或自噬的抑制作用可能是七叶树素治疗癌症的联合治疗靶点。TIGAR敲低HCT-116细胞进一步增强了七叶皂苷诱导的ROS升高和自噬激活。但是，敲低自噬相关基因ATG5或3-甲基腺嘌呤（3-MA）的自噬抑制作用会在TIGAR被敲低时夸大了七叶皂苷诱导的细胞凋亡。总之，TIGAR通过抑制细胞凋亡和响应自发七叶树的自噬而在确定癌细胞命运方面起着双重作用，这表明TIGAR和/或自噬的抑制作用可能是七叶树胶治疗癌症的联合治疗靶点。