Abstract

DNA damage-inducible transcript 4 (DDIT4) is known to participate in various cancers, including glioblastoma multiforme (GBM). However, contradictory roles of DDIT4 exist in inducing cell death and possessing anti-apoptotic functions against cancer progression. Herein, we investigated DDIT4 signaling in GBM and temozolomide (TMZ) drug resistance. We identified that TMZ induced DDIT4 upregulation, leading to desensitization against TMZ cytotoxicity in GBM cells. Higher DDIT4 levels were found in glioma cells and mesenchymal-type GBM patients, and these higher levels were positively correlated with mesenchymal markers. Furthermore, patients with lower DDIT4 levels, especially O-6-methylguanine-DNA methyltransferase (MGMT)-methylated patients, exhibited better TMZ therapeutic efficacy. We determined that higher levels of 5 DDIT4-associated downstream genes, including SLC2A3 (also known as glucose transporter 3 (GLUT3)), can be used to predict a poor prognosis. Among these 5 genes, only GLUT3 was upregulated in both TMZ-treated and DDIT4-overexpressing cells. DDIT4-mediated GLUT3 expression was also identified, and its expression decreased TMZ’s cytotoxicity. A significant correlation existed between DDIT4 and GLUT3. DDIT4 signaling was found to be involved in both glycolytic and autophagic pathways. However, GLUT3 only participated in the exhibition of DDIT4-mediated stemness, resulting from glycolytic regulation, but not in DDIT4-mediated autophagic signaling. Finally, we identified TMZ-upregulated activating transcription factor 4 (ATF4) as an upstream regulator of DDIT4-mediated GLUT3/stemness signaling and autophagy. Consequently, ATF4/DDIT4 signaling was connected to both autophagy and GLUT3-regulated stemness, which are involved in TMZ drug resistance and the poor prognoses of GBM patients. Targeting DDIT4/GLUT3 signaling might be a new direction for glioma therapy.

中文翻译：

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DNA 损伤诱导转录物 4 (DDIT4) 的关键作用是将自噬和 GLUT3 介导的干性联系起来，使替莫唑胺在胶质母细胞瘤中的疗效脱敏

 抽象的

DNA 损伤诱导转录物 4 (DDIT4) 已知参与多种癌症，包括多形性胶质母细胞瘤 (GBM)。然而，DDIT4 在诱导细胞死亡和具有对抗癌症进展的抗凋亡功能方面存在矛盾的作用。在此，我们研究了 GBM 和替莫唑胺 (TMZ) 耐药性中的 DDIT4 信号传导。我们发现 TMZ 诱导 DDIT4 上调，导致 GBM 细胞对 TMZ 细胞毒性脱敏。在胶质瘤细胞和间充质型 GBM 患者中发现较高的 DDIT4 水平，并且这些较高水平与间充质标志物呈正相关。此外，DDIT4水平较低的患者，尤其是O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）甲基化的患者，表现出更好的TMZ治疗效果。我们确定，包括 SLC2A3（也称为葡萄糖转运蛋白 3 (GLUT3)）在内的 5 个 DDIT4 相关下游基因的较高水平可用于预测不良预后。在这 5 个基因中，只有 GLUT3 在 TMZ 处理和 DDIT4 过表达细胞中均上调。还鉴定了 DDIT4 介导的 GLUT3 表达，其表达降低了 TMZ 的细胞毒性。 DDIT4 和 GLUT3 之间存在显着相关性。 DDIT4 信号传导被发现参与糖酵解和自噬途径。然而，GLUT3仅参与由糖酵解调节引起的DDIT4介导的干性的表现，而不参与DDIT4介导的自噬信号传导。最后，我们发现 TMZ 上调的激活转录因子 4 (ATF4) 是 DDIT4 介导的 GLUT3/干细胞信号和自噬的上游调节因子。 因此，ATF4/DDIT4 信号传导与自噬和 GLUT3 调节的干性有关，这与 TMZ 耐药性和 GBM 患者的不良预后有关。靶向 DDIT4/GLUT3 信号传导可能是神经胶质瘤治疗的新方向。