Department of Biology, The University of Texas Rio Grande Valley, 1201 W., Edinburg, TX 78539, USA.
Cells. 2021 Nov 7;10(11):3065. doi: 10.3390/cells10113065.
Glioblastoma (GBM) is the most lethal primary brain cancer that lacks effective molecular targeted therapies. The PI3K/AKT/mTOR pathway is activated in 90% of all Glioblastoma multiforme (GBM) tumors. To gain insight into the impact of the PI3K pathway on GBM metabolism, we treated U87MG GBM cells with NVP-BEZ235 (PI3K and mTOR a dual inhibitor) and identified differentially expressed genes with RNA-seq analysis. RNA-seq identified 7803 differentially regulated genes in response to NVP-BEZ235. Gene Set Enrichment Analysis (GSEA) identified two glycolysis-related gene sets that were significantly enriched ( 0.05) in control samples compared to NVP-BEZ235-treated samples. We validated the inhibition of glycolytic genes by NVP-BEZ235 and examined the impact of the FOXO1 inhibitor (AS1842856) on these genes in a set of GBM cell lines. FOXO1 inhibition alone was associated with reduced expression, but not or . Bioinformatics analyses revealed that PI3K-impacted glycolytic genes were over-expressed and co-expressed in GBM clinical samples. The elevated expression of PI3K-impacted glycolytic genes was associated with poor prognosis in GBM based on Kaplan-Meier survival analyses. Our results suggest novel insights into hallmark metabolic reprogramming associated with the PI3K-mTOR dual inhibition.
胶质母细胞瘤（GBM）是最致命的原发性脑癌，缺乏有效的分子靶向治疗方法。PI3K/AKT/mTOR 通路在所有多形性胶质母细胞瘤（GBM）肿瘤中激活了 90%。为了深入了解 PI3K 通路对 GBM 代谢的影响，我们用 NVP-BEZ235（PI3K 和 mTOR 的双重抑制剂）处理 U87MG GBM 细胞，并通过 RNA-seq 分析鉴定差异表达基因。RNA-seq 鉴定出 7803 个对 NVP-BEZ235 反应差异调节的基因。基因集富集分析（GSEA）发现，与 NVP-BEZ235 处理的样本相比，两个与糖酵解相关的基因集在对照样本中显著富集（0.05）。我们验证了 NVP-BEZ235 对糖酵解基因的抑制作用，并在一组 GBM 细胞系中检查了 FOXO1 抑制剂（AS1842856）对这些基因的影响。FOXO1 抑制单独与降低表达相关，但不与 或 相关。生物信息学分析显示，PI3K 影响的糖酵解基因在 GBM 临床样本中过度表达和共表达。PI3K 影响的糖酵解基因的高表达与 GBM 基于 Kaplan-Meier 生存分析的不良预后相关。我们的研究结果为 PI3K-mTOR 双重抑制相关的标志性代谢重编程提供了新的见解。
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