Glioblastomas are characterized by fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from EGFR via mammalian target of rapamycin complex 1 (mTORC1) is a major driver of cell growth and proliferation and one of the most commonly altered signalling pathways in glioblastomas. Therefore, epidermal growth factor receptor and mTORC1 signalling are plausible therapeutic targets and clinical trials with inhibitors are in progress. However, we have previously shown that epidermal growth factor receptor and mTORC1 inhibition triggers metabolic changes leading to adverse effects under the conditions of the tumour microenvironment by protecting from hypoxia-induced cell death. We hypothesized that conversely mTORC1 activation sensitizes glioma cells to hypoxia-induced cell death. As a model for mTORC1 activation we used gene suppression of its physiological inhibitor TSC2 (TSC2sh). TSC2sh glioma cells showed increased sensitivity to hypoxia-induced cell death that was accompanied by an earlier ATP depletion and an increase in reactive oxygen species. There was no difference in extracellular glucose consumption but an altered intracellular metabolic profile with an increase of intermediates of the pentose phosphate pathway. Mechanistically, mTORC1 upregulated the first and rate limiting enzyme of the pentose phosphate pathway, G6PD. Furthermore, an increase in oxygen consumption in TSC2sh cells was detected. This appeared to be due to higher transcription rates of genes involved in mitochondrial respiratory function including PPARGC1A and PPARGC1B (also known as PGC-1α and -β). The finding that mTORC1 activation causes an increase in oxygen consumption and renders malignant glioma cells susceptible to hypoxia and nutrient deprivation could help identify glioblastoma patient cohorts more likely to benefit from hypoxia-inducing therapies such as the VEGFA-targeting antibody bevacizumab in future clinical evaluations.

中文翻译：

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雷帕霉素复合物1活化的哺乳动物靶标使人神经胶质瘤细胞对缺氧诱导的细胞死亡敏感

胶质母细胞瘤的特征在于快速不受控制的生长，导致缺氧区域和坏死。通过哺乳动物雷帕霉素复合物1（mTORC1）的靶标从EGFR发出的信号是细胞生长和增殖的主要驱动力，也是胶质母细胞瘤中最常改变的信号途径之一。因此，表皮生长因子受体和mTORC1信号是可能的治疗靶点，并且抑制剂的临床试验正在进行中。但是，我们以前已经表明，表皮生长因子受体和mTORC1抑制可通过防止缺氧引起的细胞死亡，在肿瘤微环境条件下触发代谢变化，从而导致不良反应。我们假设相反地，mTORC1激活使神经胶质瘤细胞对缺氧诱导的细胞死亡敏感。作为mTORC1激活的模型，我们使用了其生理抑制剂TSC2（TSC2sh）的基因抑制。TSC2sh神经胶质瘤细胞显示出对缺氧诱导的细胞死亡的敏感性增加，并伴随着较早的ATP消耗和活性氧的增加。细胞外葡萄糖消耗没有差异，但是随着戊糖磷酸途径中间物的增加，细胞内代谢特征发生了改变。从机理上讲，mTORC1上调了戊糖磷酸途径的第一个酶和限速酶G6PD。此外，检测到TSC2sh细胞的耗氧量增加。这似乎是由于参与线粒体呼吸功能的基因的转录率较高，包括 TSC2sh神经胶质瘤细胞显示出对缺氧诱导的细胞死亡的敏感性增加，并伴随着较早的ATP消耗和活性氧的增加。细胞外葡萄糖消耗没有差异，但是随着戊糖磷酸途径中间物的增加，细胞内代谢特征发生了改变。从机理上讲，mTORC1上调了戊糖磷酸途径的第一个酶和限速酶G6PD。此外，检测到TSC2sh细胞的耗氧量增加。这似乎是由于参与线粒体呼吸功能的基因的转录率较高，包括 TSC2sh神经胶质瘤细胞显示出对缺氧诱导的细胞死亡的敏感性增加，并伴随着较早的ATP消耗和活性氧的增加。细胞外葡萄糖消耗没有差异，但是随着戊糖磷酸途径中间物的增加，细胞内代谢特征发生了改变。从机理上讲，mTORC1上调了戊糖磷酸途径的第一个酶和限速酶G6PD。此外，检测到TSC2sh细胞的耗氧量增加。这似乎是由于参与线粒体呼吸功能的基因的转录率较高，包括 细胞外葡萄糖消耗没有差异，但是随着戊糖磷酸途径中间物的增加，细胞内代谢特征发生了改变。从机理上讲，mTORC1上调了戊糖磷酸途径的第一个酶和限速酶G6PD。此外，检测到TSC2sh细胞的耗氧量增加。这似乎是由于参与线粒体呼吸功能的基因的转录率较高，包括 细胞外葡萄糖消耗没有差异，但是随着戊糖磷酸途径中间物的增加，细胞内代谢特征发生了改变。从机理上讲，mTORC1上调了戊糖磷酸途径的第一个酶和限速酶G6PD。此外，检测到TSC2sh细胞的耗氧量增加。这似乎是由于参与线粒体呼吸功能的基因的转录率较高，包括PPARGC1A和PPARGC1B（也称为PGC-1α和-β）。mTORC1激活会导致耗氧量增加并使恶性神经胶质瘤细胞易发生缺氧和营养缺乏的发现可能有助于鉴定胶质母细胞瘤患者人群，这些人群在未来的临床评估中更可能受益于低氧诱导疗法，例如靶向VEGFA的抗体贝伐单抗。