焦亡是细胞程序性死亡的一种形式,最近被描述为化疗药物治疗肿瘤的一种新的分子机制。Miltirone,从丹参根中分离出的菲醌衍生物,已被证明具有抗癌活性。这里,我们发现米替龙抑制HepG2或Hepa1-6细胞的细胞活力,并在每个肝细胞癌(HCC)细胞系中诱导gasderminE(GSDME)的蛋白水解裂解,伴随着caspase3的裂解。敲除GSDME将米替龙诱导的细胞死亡从焦凋亡转变为凋亡。此外,通过siRNA介导的半胱天冬酶三沉默和特异性半胱天冬酶三抑制剂Z-DEVD-FMK减弱米替龙对GSDME依赖性细胞凋亡的诱导作用,分别。米替龙有效地引起细胞内活性氧(ROS)的积累,并抑制丝裂原激活和细胞外信号调节激酶(MEK)和细胞外调节蛋白激酶1/2(ERK1/2)的磷酸化,以诱导细胞凋亡。此外,米替龙在Hepa1-6小鼠同系肝癌模型中显著抑制肿瘤生长并诱导细胞凋亡。这些结果提供了新的见解,即米替龙是通过GSDME依赖性焦亡治疗HCC的潜在治疗剂。
Pyroptosis is a form of programmed cell death, and recently described as a new molecular mechanism of chemotherapy drugs in the treatment of tumors. Miltirone, a derivative of phenanthrene-quinone isolated from the root of Salvia miltiorrhiza Bunge, has been shown to possess anti-cancer activities. Here, we found that miltirone inhibited the cell viability of either HepG2 or Hepa1-6 cells, and induced the proteolytic cleavage of gasdermin E (GSDME) in each hepatocellular carcinoma (HCC) cell line, with concomitant cleavage of caspase 3. Knocking out GSDME switched miltirone-induced cell death from pyroptosis to apoptosis. Additionally, the induction effects of miltirone on GSDME-dependent pyroptosis were attenuated by siRNA-mediated caspase three silencing and the specific caspase three inhibitor Z-DEVD-FMK, respectively. Miltirone effectively elicited intracellular accumulation of reactive oxygen species (ROS), and suppressed phosphorylation of mitogen-activated and extracellular signal-regulated kinase (MEK) and extracellular regulated protein kinases 1/2 (ERK1/2) for pyroptosis induction. Moreover, miltirone significantly inhibited tumor growth and induced pyroptosis in the Hepa1-6 mouse HCC syngeneic model. These results provide a new insight that miltirone is a potential therapeutic agent for the treatment of HCC via GSDME-dependent pyroptosis.