HDAC inhibitors reverse the Warburg Effect and Elicit Metabolic Vulnerabilities in Model Systems of Glioblastoma

HDAC 抑制剂逆转 Warburg 效应并引发胶质母细胞瘤模型系统中的代谢脆弱性

• 批准号: 10209026
• 负责人: MARKUS D SIEGELIN
• 金额: $ 40.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209026
• 关键词: Acute; Adult; Animals; Apoptosis; Autophagocytosis; Binding; Biological Models; Brain Neoplasms; Carbon Isotopes; Cell Respiration; Cells; Cellular Metabolic Process; ChIP-seq; Clinical; Coupled; Dependence; Diagnosis; Digestion; Disease; Disease Progression; Down-Regulation; Energy Metabolism; Enhancers; Enzymes; Epigenetic Process; FDA approved; Gene set enrichment analysis; Genes; Genetic; Glioblastoma; Glioma; Glucose; Glycolysis; Goals; HDAC1 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; In Vitro; Life Expectancy; Link; Lipids; Lysosomes; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Multiple Myeloma; Mus; Nonesterified Fatty Acids; Oxidative Phosphorylation; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Primary Brain Neoplasms; Process; Production; Prognosis; Promoter Regions; Research; Role; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Time; Translations; United States; Vorinostat; Warburg Effect; aerobic glycolysis; antitumor effect; base; c-myc Genes; combat; etomoxir; experimental study; extracellular; fatty acid oxidation; in vivo; in vivo Model; inhibitor/antagonist; innovation; molecular subtypes; neoplastic cell; novel; oxidation; patient derived xenograft model; pre-clinical; public health relevance; resistance mechanism; stable isotope; standard of care; stem; temozolomide; therapy resistant; transcription factor; transcriptome; treatment strategy; tumor; tumor metabolism

Glioblastoma multiforme (GBM) is the most common primary brain tumor with about 8500 cases diagnosed each year in the United States. Within a time frame of roughly one year almost all patients succumb to this detrimental disease despite treatment. Therefore, novel, ideally tumor specific approaches are necessary to combat these tumors. Akin to other malignancies, GBMs depend on aerobic glycolysis, meaning that paradoxically glucose is metabolized to lactate in the presence of an abundance of molecular oxygen (Warburg-effect). Based on a chromatin immunoprecipitation sequencing and transcriptome analysis, we found that HDAC-inhibition through panobinostat, vorinostat and FK228 results in reprogramming of metabolism in stem-like and established GBM cells, which is orchestrated in part by the modulation of three key transcription factors. This leads to a significant reduction of glycolysis (reversal of the Warburg effect) with lower overall ATP levels. HDAC treated GBM cells reactivate oxidative phosphorylation (OXPHOS). Consistently, interference with mitochondrial translation or ATP production enhanced apoptosis in stem-like glioma and patient derived xenograft (PDX) cells. To fuel OXPHOS, HDAC treated glioblastoma cells increased the levels of transporters and enzymes related to fatty acid oxidation (FAO) and pharmacological inhibition of FAO by the clinically validated compound, Etomoxir, synergistically induced apoptosis in PDX, stem-like and established glioblastoma cells in vitro as well as in PDX models in vivo. Overall, this research will enhance our understanding about the treatment of brain tumors and may potentially allow us to formulate a novel treatment strategy for glioblastomas and other gliomas.

多形性胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，约有 美国每年诊断出8500例病例。在大约的时间范围内 一年来，尽管接受了治疗，几乎所有患者都死于这种有害疾病。 因此，需要新的、理想的肿瘤特异性方法来对抗这些 肿瘤。与其他恶性肿瘤类似，GBM 依赖于有氧糖酵解，这意味着 矛盾的是，在存在大量葡萄糖的情况下，葡萄糖会代谢为乳酸。 分子氧（瓦尔堡效应）。基于染色质免疫沉淀 测序和转录组分析，我们发现 HDAC 抑制通过 帕比司他、伏立诺他和 FK228 导致干细胞代谢重编程 并建立了 GBM 细胞，该细胞部分是通过三个关键的调节来协调的 转录因子。这导致糖酵解显着减少（逆转 Warburg 效应），总 ATP 水平较低。 HDAC 处理的 GBM 细胞重新激活 氧化磷酸化（OXPHOS）。一致地，干扰线粒体 翻译或 ATP 产生增强干细胞样神经胶质瘤和患者的细胞凋亡 衍生的异种移植（PDX）细胞。为 OXPHOS、HDAC 处理的胶质母细胞瘤细胞提供能量 增加与脂肪酸氧化相关的转运蛋白和酶的水平（FAO） 以及经临床验证的化合物 Etomoxir 对 FAO 的药理抑制作用， 协同诱导 PDX、干细胞样和已建立的胶质母细胞瘤细胞凋亡 体外以及体内 PDX 模型。总的来说，这项研究将增强我们的 了解脑肿瘤的治疗并可能使我们能够 制定胶质母细胞瘤和其他胶质瘤的新治疗策略。