背景:角化是一种独特的铜依赖性细胞死亡形式,与细胞的代谢状态高度相关。雷公藤甲素通过改变金属离子的调节发挥药理活性。在癌症中,人们对它的了解很少,所以在这项研究中,我们探讨了雷公藤甲素是否可以诱导宫颈癌细胞凋亡。
方法:人宫颈癌细胞系HeLa和SiHa,主要依赖于氧化磷酸化,用雷公藤甲素治疗。细胞活力,扩散和迁移,在这些细胞系中评估铜水平和角化相关蛋白水平。施用铜离子螯合剂四硫钼酸盐(TTM)以确定其是否可以逆转雷公藤甲素诱导的角化作用。此外,建立了裸鼠宫颈癌异种移植模型,以确定雷公藤甲素对离体肿瘤组织中细胞凋亡的影响。
结果:铜浓度随雷公藤甲素处理而增加。角化相关蛋白的水平,如FDX1、LIAS、和DLAT,在HeLa和SiHa细胞系中,雷公藤甲素处理降低。XIAP,雷公藤甲素的目标,通过调节COMMD1在角化中发挥作用。铜出口国(ATP7A/B)水平下降,但是铜导入体(CTR1)的水平没有随着雷公藤甲素的治疗而改变。此外,雷公藤甲素在体内抑制宫颈癌生长并诱导角化。
结论:总之,我们报道了一种新的抗肿瘤机制,雷公藤甲素通过调节XIAP/COMMD1/ATP7A/B轴破坏细胞内铜稳态并诱导宫颈癌细胞凋亡。
BACKGROUND: Cuproptosis is a unique copper-dependent form of cell death that is highly correlated with the metabolic state of cells. Triptolide exerts pharmacological activity by altering the regulation of metal ions. Cuproptosis is poorly understood in cancer, so in this study, we explored whether triptolide could induce cuproptosis in cervical cancer cells.
METHODS: The human cervical cancer cell lines HeLa and SiHa, which primarily rely on oxidative phosphorylation, were treated with triptolide. Cell viability, proliferation and migration, copper levels and cuproptosis-related protein levels were evaluated in these cell lines. The copper ion chelator tetrathiomolybdate (TTM) was administered to determine whether it could reverse the cuproptosis induced by triptolide. In addition, a nude mouse cervical cancer xenograft model was established to determine the effects of triptolide on cuproptosis in isolated tumor tissues.
RESULTS: The copper concentration increased with triptolide treatment. The levels of cuproptosis -related proteins, such as FDX1, LIAS, and DLAT, in the HeLa and SiHa cell lines decreased with triptolide treatment. XIAP, the target of triptolide, played a role in cuproptosis by regulating COMMD1. The level of copper exporters (ATP7A/B) decreased, but the level of the copper importer (CTR1) did not change with triptolide treatment. Furthermore, triptolide inhibited cervical cancer growth and induced cuproptosis in vivo.
CONCLUSIONS: In summary, we report a new antitumor mechanism by which triptolide disrupted intracellular copper homeostasis and induced cuproptosis in cervical cancer by regulating the XIAP/COMMD1/ATP7A/B axis.