Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China.
Department of Anesthesiology, First Hospital of Jilin University, Changchun, 130021, China.
Biochem Biophys Res Commun. 2019 Oct 20;518(3):590-597. doi: 10.1016/j.bbrc.2019.08.096. Epub 2019 Aug 21.
RSL3 is a type of small molecular compound which can inactivate glutathione peroxidase 4 (GPX4) and induce ferroptosis, but its role in glioma cell death remains unclear. In this study, we found RSL3 inhibited the viabilities of glioma cells and induced glioma cell death in a dose-dependent manner. In vitro studies revealed that RSL3-induced cell death was accompanied with the changes of autophagy-associated protein levels and was alleviated by pretreatment of 3-Methyladenine, bafilomycin A1 and knockdown of ATG5 with siRNA. The ATP and pyruvate content as well as the protein levels of HKII, PFKP, PKM2 were decreased in cells treated by RSL3, indicating that RSL3 induced glycolysis dysfunction in glioma cells. Moreover, supplement of exterior sodium pyruvate, which was a final product of glycolysis, not only inhibited the changes of autophagy-associated protein levels caused by RSL3, but also prevented RSL3-induced cell death. In vivo data suggested that the inhibitory effect of RSL3 on the growth of glioma cells was associated with glycolysis dysfunction and autophagy activation. Taken together, RSL3 induced autophagic cell death in glioma cells via causing glycolysis dysfunction.
RSL3 是一种小分子化合物，可使谷胱甘肽过氧化物酶 4（GPX4）失活并诱导铁死亡，但它在神经胶质瘤细胞死亡中的作用尚不清楚。在本研究中，我们发现 RSL3 可抑制神经胶质瘤细胞的活力并呈剂量依赖性诱导神经胶质瘤细胞死亡。体外研究表明，RSL3 诱导的细胞死亡伴随着自噬相关蛋白水平的变化，并且可以通过 3-甲基腺嘌呤、巴弗洛霉素 A1 和 siRNA 敲低 ATG5 预处理来减轻。RSL3 处理的细胞中 ATP 和丙酮酸含量以及 HKII、PFKP、PKM2 蛋白水平降低，表明 RSL3 诱导神经胶质瘤细胞糖酵解功能障碍。此外，外源性丙酮酸（糖酵解的终产物）的补充不仅抑制了 RSL3 引起的自噬相关蛋白水平的变化，而且还阻止了 RSL3 诱导的细胞死亡。体内数据表明，RSL3 对神经胶质瘤细胞生长的抑制作用与糖酵解功能障碍和自噬激活有关。总之，RSL3 通过引起糖酵解功能障碍诱导神经胶质瘤细胞发生自噬性细胞死亡。
