Dr Senckenberg Institute of Neurooncology, Goethe University, Frankfurt, Germany.
Department of Neurology, University Hospital Basel, Switzerland.
J Neurochem. 2018 Feb;144(4):421-430. doi: 10.1111/jnc.14264. Epub 2018 Jan 8.
Although bevacizumab initially shows high response rates in gliomas and other tumours, therapy resistance usually develops later. Because anti-angiogenic agents are supposed to induce hypoxia, we asked whether rendering glioma cells independent of oxidative phosphorylation modulates their sensitivity against hypoxia and bevacizumab. LNT-229 glioma cells without functional mitochondria (rho ) and control (rho ) cells were generated. LNT-229 rho -cells displayed reduced expression of oxidative phosphorylation-related genes and diminished oxygen consumption. Conversely, glycolysis was up-regulated in these cells, as shown by increased lactate production and stronger expression of glucose transporter-1 and lactate dehydrogenase-A. However, hypoxia-induced cell death in vitro was nearly completely abolished in the LNT-229 rho -cells, these cells were more sensitive towards glucose restriction and the treatment with the glycolysis inhibitor 2-deoxy-D-glucose. In an orthotopic mouse xenograft experiment, bevacizumab induced hypoxia as reflected by elevated Hypoxia-inducible factor 1-alpha staining in both, rho - and rho -tumours. However, it prolonged survival only in the mice bearing rho -tumours (74 days vs. 105 days, p = 0.024 log-rank test) and had no effect on survival in mice carrying LNT-229 rho -tumours (75 days vs. 70 days, p = 0.52 log-rank test). Interestingly, inhibition of glycolysis in vivo with 2-deoxy-D-glucose re-established sensitivity of rho -tumours against bevacizumab (98 days vs. 80 days, p = 0.0001). In summary, ablation of oxidative phosphorylation in glioma cells leads to a more glycolytic and hypoxia-resistant phenotype and is sufficient to induce bevacizumab-refractory tumours. These results add to increasing evidence that a switch towards glycolysis is one mechanism how tumour cells may evade anti-angiogenic treatments and suggest anti-glycolytic strategies as promising approaches to overcome bevacizumab resistance.
尽管贝伐单抗最初在神经胶质瘤和其他肿瘤中显示出高反应率，但通常会在后期产生耐药性。由于抗血管生成剂被认为会诱导缺氧，我们想知道使神经胶质瘤细胞独立于氧化磷酸化是否会调节它们对缺氧和贝伐单抗的敏感性。生成了缺乏功能性线粒体（rho-）的 LNT-229 神经胶质瘤细胞和对照（rho+）细胞。LNT-229 rho-细胞表现出氧化磷酸化相关基因表达减少和耗氧量降低。相反，这些细胞中的糖酵解被上调，表现为乳酸产量增加和葡萄糖转运蛋白-1 和乳酸脱氢酶-A 的表达增强。然而，在 LNT-229 rho-细胞中，体外缺氧诱导的细胞死亡几乎完全被消除，这些细胞对葡萄糖限制和糖酵解抑制剂 2-脱氧-D-葡萄糖的治疗更为敏感。在原位小鼠异种移植实验中，贝伐单抗诱导了 rho-和 rho+肿瘤中缺氧诱导因子 1-alpha 染色升高所反映的缺氧。然而，它仅延长了携带 rho-肿瘤的小鼠的存活时间（74 天对 105 天，p=0.024 对数秩检验），对携带 LNT-229 rho-肿瘤的小鼠的存活时间没有影响（75 天对 70 天，p=0.52 对数秩检验）。有趣的是，用 2-脱氧-D-葡萄糖在体内抑制糖酵解重新建立了 rho-肿瘤对贝伐单抗的敏感性（98 天对 80 天，p=0.0001）。总之，神经胶质瘤细胞中氧化磷酸化的缺失导致更具糖酵解和抗缺氧表型，足以诱导贝伐单抗耐药性肿瘤。这些结果增加了越来越多的证据表明，向糖酵解的转变是肿瘤细胞逃避抗血管生成治疗的一种机制，并表明抗糖酵解策略是克服贝伐单抗耐药性的有前途的方法。
