Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China; Department of Breast Surgery, First Hospital of Jilin University, Changchun, China.
Department of Breast Surgery, First Hospital of Jilin University, Changchun, China.
Biochim Biophys Acta Mol Basis Dis. 2022 Dec 1;1868(12):166529. doi: 10.1016/j.bbadis.2022.166529. Epub 2022 Aug 27.
RSL3 is a synthetic molecule that inactivates glutathione peroxidase 4 to induce ferroptosis. However, its effect on glioma stem cells (GSC) remains unclear. In this study, we found that RSL3 significantly suppressed GSC proliferation and induced their differentiation into astrocytes, which was accompanied by the downregulation of stemness-related markers, including Nestin and Sox2. Combined transcriptome and proteome analyses further revealed that RSL3 promoted GSC differentiation by suppressing transglutaminase 2 (Tgm2), but not by ferroptosis-related pathways. Tgm2 overexpression in CSC2078 cells rescued the changes in stemness-related markers and differentiation caused by RSL3, which was mediated by inhibitor of DNA binding 1 (ID1) activation. Further studies identified ID1 as a downstream signaling target of Tgm2. Blocking the phosphoinositide-3 kinase (PI3K)/Akt pathway with LY294002 suppressed PI3K, p-Akt, and ID1 levels but not Tgm2. Tgm2 overexpression abrogated the changes in PI3K, p-Akt, and ID1 levels caused by LY294002. Taken together, we demonstrate that RSL3 does not induce ferroptosis; instead, it inhibits GSC proliferation and triggers their differentiation by suppressing the Tgm2/Akt/ID1 signaling axis.
RSL3 是一种能使谷胱甘肽过氧化物酶 4 失活从而诱导铁死亡的合成分子。然而，其对神经胶质瘤干细胞（GSC）的影响尚不清楚。在这项研究中，我们发现 RSL3 能显著抑制 GSC 的增殖，并诱导其向星形胶质细胞分化，这伴随着干性相关标志物（包括 Nestin 和 Sox2）的下调。联合转录组和蛋白质组分析进一步表明，RSL3 通过抑制转谷氨酰胺酶 2（Tgm2）而非铁死亡相关途径来促进 GSC 分化。在 CSC2078 细胞中转染 Tgm2 过表达挽救了 RSL3 引起的干性相关标志物和分化变化，这是由 DNA 结合抑制因子 1（ID1）激活介导的。进一步的研究确定 ID1 是 Tgm2 的下游信号靶标。用 LY294002 阻断磷酸肌醇 3-激酶（PI3K）/Akt 通路抑制了 PI3K、p-Akt 和 ID1 的水平，但不抑制 Tgm2。Tgm2 过表达消除了 LY294002 引起的 PI3K、p-Akt 和 ID1 水平的变化。综上所述，我们证明 RSL3 不会诱导铁死亡；相反，它通过抑制 Tgm2/Akt/ID1 信号轴抑制 GSC 增殖并触发其分化。
