Drivers of Metabolic Plasticity Promote Radiation Resistance in Glioblastoma Multiforme

项目摘要 摘要多形性胶质母细胞瘤(Gbm)是最耐药的肿瘤之一，其5年生存率令人沮丧。 10%的税率。对放射治疗的固有和获得性抵抗显著地导致了难治性 这些肿瘤的性质。电离辐射(IR)的细胞毒性作用主要是通过产生游离 自由基，特别是活性氧基(ROS)。因此，缓和氧化还原对缓解 IR的致死作用，增加RT的有效性。在这项建议中，我们假设基底膜肿瘤 可以通过重新连接它们的代谢来产生对RT的抗氧化反应，这是一个主要的机制 导致了他们的生存和治疗失败。到目前为止，人们对GBM的代谢反应知之甚少。 进行RT和代谢可塑性的分子驱动因素尚不清楚。在家长奖中，我们 为辐射诱导的GBM代谢重编程提供证据，包括增强的 受辐射的GBM细胞对葡萄糖和谷氨酰胺的消耗及糖酵解的分流 中间产物进入抗氧化剂，产生NADPH的磷酸戊糖途径(PPP)。基于 初步研究，我们假设IR诱导的GBM代谢重编程是精心策划的 部分是通过激活转录因子NRF2，从而启动新陈代谢的转录 驱动PPP的酶。我们还假设糖酵解中间体转移到PPP是 通过IR诱导对氧化还原敏感的糖酵解酶PKM2的抑制而进一步放大。 在这里，我们建议根据指向丝氨酸的新的令人信服的数据来扩展我们目前的工作模式 合成途径(SSP)作为辐射诱导的另一条代谢途径，也有助于 基底膜中的代谢重联。辐射增强的SSP活动是由NRF2驱动的，与NRF2一致 作为IR诱导的GBM代谢重编程的协调者。然而，我们也展示了 IR激活HIF-1途径不依赖于缺氧和IR诱导的SSP酶上调 HIF-1a的抑制可以完全阻止HIF-1a的表达，这表明这两种氧化还原-1a的双重作用。 协调RT后GBM代谢重排的敏感因素驱动抗氧化剂 在PKM2阻滞剂的协助下，通过PPP和从头开始的SSP的途径和IR抵抗。 与来自家长奖项的大量数据一起，这些研究将建立一个全面的图景 辐射诱导的基底膜代谢重排将阐明旨在 改善这种可怕疾病的放射治疗结果。

Project Summary Glioblastoma multiforme (GBM) is one of the most therapy-resistant tumors, with a dismal 5-year survival rate of <10%. Intrinsic and acquired resistance to radiation therapy contributes significantly to the refractory nature of these tumors. Ionizing radiation (IR) exerts its cytotoxic effects primarily by generating free radicals, in particular reactive oxygen species (ROS). Moderating redox is therefore critical to mitigating the lethal effects of IR and increase the effectiveness of RT. In this proposal we postulate that GBM tumors can generate an antioxidant response to RT by rewiring their metabolism and this is a major mechanism leading to their survival and treatment failure. As yet, little is known about the metabolic response of GBM undergoing RT and the molecular drivers of metabolic plasticity are unknown. In the parent award we provide evidence for radiation-induced metabolic reprogramming in GBM, which includes enhanced consumption of glucose and glutamine by irradiated GBM cells and diversion of the flow of glycolytic intermediates into the antioxidant, NADPH-producing pentose phosphate pathway (PPP). Based on preliminary studies, we hypothesize that the IR-induced metabolic reprogramming in GBM is orchestrated in part by the activation of the transcription factor NRF2, which turns on the transcription of metabolic enzymes that drive the PPP. We also hypothesize that diversion of glycolytic intermediates into the PPP is further amplified by the IR-induced inhibition of the redox-sensitive, glycolytic enzyme PKM2. Here, we propose to expand our current working model based on new compelling data that point to serine synthesis pathway (SSP) as an additional radiation-induced metabolic pathway that also contributes to metabolic rewiring in GBM. The radiation-enhanced SSP activity is driven by NRF2, in keeping with NRF2 being the orchestrator of IR-induced metabolic reprogramming in GBM. However, we have also shown that IR activates the HIF-1 pathway independently of hypoxia and IR-induced upregulation of SSP enzyme expression is completely prevented by HIF-1a inhibition, suggesting dual roles for these two redox- sensitive factors in coordinating the metabolic rewiring of GBM following RT that drives antioxidant pathways and IR resistance through the PPP and de novo SSP, with assistance from PKM2 blockade. Together with the body of data from the parent award, these studies will build a comprehensive picture of radiation-induced metabolic rewiring in GBM that will illuminate interventional strategies aimed at improving RT outcomes in this dreadful disease.