Targeting nicotinamide adenosine dinucleotide (NAD) in diffuse gliomas.
Targeting nicotinamide adenosine dinucleotide (NAD) in diffuse gliomas.
复制标题
靶向弥漫性神经胶质瘤中的烟酰胺腺苷二核苷酸 (NAD)。
DOI：
10.1093/neuonc/noab265
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发表时间：
2022
期刊：
影响因子：
15.9
通讯作者：
Wu,Jing
中科院分区：
文献类型：
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作者：
Wu,Jing
弥漫性胶质瘤是最常见的原发性脑肿瘤，并且非常难以治疗，无论它们在最初诊断时是低级别胶质瘤还是侵袭性胶质母细胞瘤。由于高水平的肿瘤内和肿瘤间异质性以及由于响应于治疗的选择性压力而不断演变的基因组景观，靶向神经胶质瘤中的个体信号转导通路的治疗未能改善临床结果。尽管它们具有遗传异质性，但所有癌细胞都需要重新编程代谢途径，以平衡细胞构建模块的生物合成和足够的ATP以支持细胞生长和存活的需求。代谢重编程被认为是癌症的标志。1因此，人们越来越有兴趣开发针对肿瘤特异性代谢过程的策略，这些代谢过程对癌症（包括神经胶质瘤）至关重要。烟酰胺腺苷二核苷酸（NAD）已成为生物能量和调节过程中最重要的因素之一。2 NAD是氧化还原反应中必不可少的电子载体，参与许多代谢途径，如糖酵解、氧化磷酸化和三羧酸（TCA）循环。3 NAD水平升高通过甘油醛3-磷酸脱氢酶和乳酸脱氢酶增强糖酵解，这需要NAD作为辅酶，因此NAD的持续补充支持快速生长的癌细胞。4 NAD除了在代谢中作为辅酶的重要作用外，还是聚ADP核糖聚合酶（PARP）和Sirtuins的底物，分别介导NAD依赖的聚ADP核糖基化和去乙酰化。由于这两种功能，NAD参与了癌症中经常改变的几种关键信号传导途径，如细胞周期进展，DNA修复和代谢调节。因此，可以想象，限制NAD的可用性将抵消促进癌细胞存活的途径。补救途径被认为是维持细胞内NAD水平的关键。3烟酰胺磷酸核糖基转移酶（NAMPT）是NAD生物合成的主要限速酶，已经在临床前和临床试验环境中研究了几种特异性NAMPT抑制剂以开发潜在的抗癌治疗剂。5-7在这一期的《神经肿瘤学》中，Sharma等人通过使用新开发的NAMPT抑制剂KPT 9274研究了NAMPT抑制在调节胶质瘤细胞增殖和存活中的作用。8首先，作者证明神经胶质瘤细胞活力被NAMPT的基因敲除和药理学抑制显著抑制，表明NAMPT表达对于神经胶质瘤细胞存活是必需的。为了探索NAMPT抑制对异质性肿瘤的影响，他们在选择神经胶质瘤细胞模型进行研究时故意考虑了几个关键的生物标志物，以便细胞系代表具有各种遗传背景和不同生物学特征的神经胶质瘤，包括MGMT启动子甲基化和IDH突变。作者进一步证明了在KPT 2974诱导的NAMPT抑制后，其细胞模型中细胞增殖率降低、细胞凋亡诱导和血管生成抑制。此外，他们证明了耐药胶质瘤干细胞（GSC）的球体形成和自我更新能力降低。然后，他们检查了KPT 2974对胶质瘤细胞代谢的影响，并分别通过Seahorse测定和MitoTracker染色发现基础呼吸，呼吸能力和活性细胞线粒体含量显着减少，表明KPT 2974诱导线粒体呼吸。
Diffuse gliomas are the most common primary brain tumors and are extremely difficult to treat, regardless if they are lower grade gliomas or aggressive glioblastomas at initial diagnosis. Due to the high level of intra-and inter-tumoral heterogeneity and a genomic landscape that constantly evolves due to selective pressure in response to the therapies, treatments that target individual signal transduction pathways in gliomas have failed to improve clinical outcomes. Despite their genetic heterogeneity, all cancer cells need to reprogram metabolic pathways to balance the need for biosynthesis of cell building blocks and sufficient ATP to support cell growth and survival. Metabolic reprogramming is considered a hallmark of cancer. 1 Therefore, there is a growing interest in developing strategies to target tumor-specific metabolic processes that are critical for cancers, including gliomas. Nicotinamide adenosine dinucleotide (NAD) has emerged as one of the most important factors involved in both bioenergetic and regulatory processes. 2 NAD is an essential electron carrier in redox reactions involved in a number of metabolic pathways such as glycolysis, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle. 3 An elevated level of NAD enhances glycolysis via glyceraldehyde 3-phosphate dehydrogenase and lactate dehydrogenase, which require NAD as a coenzyme, and thus continuous replenishment of NAD supports fast-growing cancer cells. 4 Besides its critical role as a coenzyme in metabolism, NAD is a substrate of poly (ADP-ribose) polymerase (PARP) and Sirtuins, mediating the NAD-dependent poly-ADP ribosylation and deacetylation, respectively. Because of both functions, NAD is involved in several key signaling pathways that are often altered in cancer, such as cell cycle progression, DNA repair, and metabolic regulation. Therefore, it is conceivable that limiting the availability of NAD would counteract pathways promoting cancer cell survival. The salvage pathway is considered critical in maintaining intracellular levels of NAD. 3 Nicotinamide phosphoribosyltransferase (NAMPT) is the major rate-limiting enzyme for NAD biosynthesis, and several specific NAMPT inhibitors have been investigated in both preclinical and clinical trial settings to develop potential anticancer therapeutics. 5–7 In this issue of Neuro-Oncology, Sharma et al investigated the role of NAMPT inhibition in regulating glioma cell proliferation and survival by using KPT9274, a newly developed NAMPT inhibitor. 8 First, the authors demonstrated that glioma cell viability was significantly suppressed by both genetic knockout and pharmacological inhibition of NAMPT, suggesting that NAMPT expression is essential for glioma cell survival. In order to explore the impact of the NAMPT inhibition on a heterogenous tumor, they deliberately factored in several key biomarkers when selecting glioma cell models for the study, so that the cell lines represent gliomas with a variety of genetic backgrounds and distinct biological features, including MGMT promoter methylation and IDH mutation. The authors further demonstrated reduced cell proliferation rate, apoptosis induction, and angiogenesis inhibition in their cell models following KPT2974-induced NAMPT inhibition. In addition, they demonstrated reduced sphere formation and self-renewal ability of resistant glioma stem-like cells (GSCs). They then examined the effects of KPT2974 on glioma cell metabolism and found a significant reduction in basal respiration, respiration capacity, and active cellular mitochondrial content via Seahorse assay and MitoTracker staining, respectively, indicating that KPT2974 induces mitochondrial …