Brucker Daniel P, Maurer Gabriele D, Harter Patrick N, Rieger Johannes, Steinbach Joachim P
Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany.
Institute of Neurology (Edinger Institute), Goethe University Hospital, Frankfurt, Germany.
Int J Oncol. 2016 Dec;49(6):2399-2410. doi: 10.3892/ijo.2016.3760. Epub 2016 Nov 4.
Forkhead box O (FOXO) transcription factors are homeostatic regulators adjusting diverse cellular processes crucial for metabolism and survival. In gliomas, FOXOs have been shown to modulate cell death, proliferation and differentiation. Here, we investigated the role of FOXO3a in human malignant gliomas with special regard to starvation conditions. Expression of FOXO3a increased with WHO grade and was accentuated in the perinecrotic niche, colocalizing with hypoxia‑inducible factor 1α (HIF1α) expression. FOXO3a was upregulated in hypoxia and translocation of FOXO3a from the cytoplasm to the nucleus was induced by serum starvation, pharmacological inhibition of protein kinase B (PKB) and hypoxia. Overexpression of FOXO3a induced tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) expression and resulted in spontaneous cell death. Knockdown of FOXO3a (shFOXO3a), on the one hand, enhanced the sensitivity of glioma cells towards H2O2 under normoxia. On the other hand, it decreased consumption of glucose and oxygen, resulting in improved survival during glucose and oxygen deprivation. Mechanistically, in shFOXO3a cells, hypoxia‑response element reporter activity, as well as the expression of common HIF1α target genes, was increased, suggesting disinhibited HIF1α signaling. However, glucose transporter 1 (GLUT1) expression was inversely regulated, and this may have been caused by an upregulation of TP53 in shFOXO3a cells. These data reveal a novel role of FOXO3a‑dependent gene regulation in the complex adaptive responses of gliomas towards starvation signals. Strategies that target FOXO3a function may directly or indirectly alter glioma cell behavior and viability in the hypoxic niche.
叉头框O（FOXO）转录因子是稳态调节因子，可调节对新陈代谢和生存至关重要的多种细胞过程。在胶质瘤中，FOXOs已被证明可调节细胞死亡、增殖和分化。在此，我们研究了FOXO3a在人类恶性胶质瘤中的作用，特别关注饥饿条件。FOXO3a的表达随世界卫生组织（WHO）分级增加，并在坏死周围微环境中增强，与缺氧诱导因子1α（HIF1α）的表达共定位。FOXO3a在缺氧状态下上调，血清饥饿、蛋白激酶B（PKB）的药理学抑制和缺氧可诱导FOXO3a从细胞质向细胞核的转位。FOXO3a的过表达诱导肿瘤坏死因子相关凋亡诱导配体（TRAIL）的表达，并导致自发细胞死亡。一方面，敲低FOXO3a（shFOXO3a）可增强胶质瘤细胞在常氧条件下对H2O2的敏感性。另一方面，它减少了葡萄糖和氧气的消耗，从而在葡萄糖和氧气剥夺期间提高了存活率。机制上，在shFOXO3a细胞中，缺氧反应元件报告基因活性以及常见HIF1α靶基因的表达增加，提示HIF1α信号传导不受抑制。然而，葡萄糖转运蛋白1（GLUT1）的表达受到反向调节，这可能是由于shFOXO3a细胞中TP53的上调所致。这些数据揭示了FOXO3a依赖性基因调控在胶质瘤对饥饿信号的复杂适应性反应中的新作用。靶向FOXO3a功能的策略可能直接或间接改变缺氧微环境中胶质瘤细胞的行为和活力。
