Hypoxia response in glioblastoma cells: effect of trehalose on macropinocytosis, autophagy and cell survival

IF 2.2 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Barbara Del Bello , Cristina Ulivieri , Emilia Maellaro
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引用次数: 0

Abstract

In glioblastoma multiforme, the most malignant brain tumor in adults, the hypoxic milieu is believed to contribute to tumor aggressiveness and resistance to therapy. Here, human glioblastoma U373-MG and T98G cells were exposed to hypoxia (1 % oxygen) or normoxia (18 % oxygen), and treated with trehalose, a natural disaccharide increasingly studied for its therapeutic potential in cancer. In all samples under hypoxia, HIF-1α stabilization was accompanied by a decrease in Nrf2 and p62/SQSTM1 proteins; redox imbalance also occurred, as documented by increased levels of ROS and parallel lowering of glutathione. Trehalose treatment increased Nrf2 and p62 proteins under normoxia, an effect lost or downsized under hypoxia. Differently, under both oxygen concentrations, trehalose increased glutathione content, consistently with its antioxidant role. In U373-MG cells, trehalose induced remarkable macropinocytosis under hypoxia, albeit less than under normoxia; on the contrary, in autophagy-proficient T98G cells, trehalose further increased the autophagic process under hypoxia compared to normoxia. As regards long-term cell fate (evaluated as colony-forming capacity), hypoxia only proved to be a favorable condition for T98G cells. However, in both cell lines, trehalose treatment significantly and dose-dependently decreased clonogenic capacity under normoxia and hypoxia; in particular, the long-lasting stimulation of macropinocytosis in U373-MG cells induced extensive cell death by methuosis. Overall, our findings suggest that trehalose-induced macropinocytosis or autophagy could also play a tumour-suppressive role in the hypoxic tumor milieu that characterizes glioblastoma, making its synergy with conventional chemotherapy and radiotherapy worth exploring.
胶质母细胞瘤细胞的缺氧反应:海藻糖对巨噬、自噬和细胞存活的影响
多形性胶质母细胞瘤是成人中最恶性的脑肿瘤,缺氧环境被认为有助于肿瘤的侵袭性和对治疗的抵抗。在这里,将人胶质母细胞瘤U373-MG和T98G细胞暴露于缺氧(1%氧气)或常氧(18%氧气)环境中,并用海藻糖处理,海藻糖是一种天然双糖,因其治疗癌症的潜力而越来越受到研究。在缺氧的所有样本中,HIF-1α稳定伴随着Nrf2和p62/SQSTM1蛋白的减少;氧化还原失衡也发生了,正如ROS水平升高和谷胱甘肽水平平行降低所证明的那样。海藻糖处理在常氧条件下增加了Nrf2和p62蛋白,在低氧条件下这种作用消失或减弱。不同的是,在两种氧浓度下,海藻糖增加谷胱甘肽含量,与其抗氧化作用一致。在U373-MG细胞中,海藻糖在缺氧条件下诱导了显著的巨噬细胞增多,尽管低于常氧条件;相反,在自噬能力强的T98G细胞中,海藻糖在低氧条件下比常氧条件下进一步增加了自噬过程。至于细胞的长期命运(以集落形成能力来评价),缺氧只对T98G细胞有利。然而,在两种细胞系中,海藻糖处理显著且剂量依赖地降低了常氧和缺氧条件下的克隆生成能力;特别是,U373-MG细胞的巨噬细胞作用的长期刺激引起了广泛的细胞死亡。总之,我们的研究结果表明海藻糖诱导的巨噬细胞或自噬也可能在胶质母细胞瘤的缺氧肿瘤环境中发挥肿瘤抑制作用,使其与常规化疗和放疗的协同作用值得探索。
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来源期刊
Biochemistry and Biophysics Reports
Biochemistry and Biophysics Reports Biochemistry, Genetics and Molecular Biology-Biophysics
CiteScore
4.60
自引率
0.00%
发文量
191
审稿时长
59 days
期刊介绍: Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.
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