Combinatory Treatment of Canavanine and Arginine Deprivation Efficiently Targets Human Glioblastoma Cells via Pleiotropic Mechanisms.
Combinatory Treatment of Canavanine and Arginine Deprivation Efficiently Targets Human Glioblastoma Cells via Pleiotropic Mechanisms.
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刀豆氨酸和精氨酸去甲肾上腺素的组合治疗通过多效性机制有效靶向人胶质母细胞瘤细胞。
DOI：
10.3390/cells9102217
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发表时间：
2020-09-30
期刊：
影响因子：
6
通讯作者：
Rędowicz MJ
中科院分区：
文献类型：
--
作者：
Karatsai O;Shliaha P;Jensen ON;Stasyk O;Rędowicz MJ
胶质母细胞瘤是原发性脑肿瘤中最常见和最具侵袭性的形式，没有有效的治疗方法。然而，它们通常表现出特定的代谢变化，包括生物合成的缺陷和对某些外源氨基酸的依赖。在这里，我们评估，在体外，一种新的组合抗胶质母细胞瘤的方法的基础上，精氨酸剥夺和刀豆氨酸，精氨酸类似物的植物来源，使用两个人胶质母细胞瘤细胞模型，U251 MG和U87 MG。组合处理深刻地影响细胞活力、形态、运动性和粘附，使细胞骨架和线粒体网络不稳定，并诱导凋亡性细胞死亡。重要的是，这种作用对胶质母细胞瘤细胞具有选择性，因为它们对原代大鼠胶质细胞不明显。在分子水平上，刀豆氨酸抑制促生存激酶，如FAK，Akt和AMPK。其对蛋白质合成和应激反应途径的影响更为复杂，并依赖于暴露时间。我们直接观察刀豆氨酸掺入新生蛋白质，通过使用定量蛋白质组学。尽管刀豆氨酸在精氨酸不存在下容易掺入多肽中，但没有观察到对这种掺入的基序偏好。我们的研究结果为进一步开发基于刀豆氨酸和精氨酸剥夺的拟议模式作为独立于血脑屏障的潜在抗胶质母细胞瘤代谢疗法提供了强有力的理论基础。
Glioblastomas are the most frequent and aggressive form of primary brain tumors with no efficient cure. However, they often exhibit specific metabolic shifts that include deficiency in the biosynthesis of and dependence on certain exogenous amino acids. Here, we evaluated, in vitro, a novel combinatory antiglioblastoma approach based on arginine deprivation and canavanine, an arginine analogue of plant origin, using two human glioblastoma cell models, U251MG and U87MG. The combinatory treatment profoundly affected cell viability, morphology, motility and adhesion, destabilizing the cytoskeleton and mitochondrial network, and induced apoptotic cell death. Importantly, the effects were selective toward glioblastoma cells, as they were not pronounced for primary rat glial cells. At the molecular level, canavanine inhibited prosurvival kinases such as FAK, Akt and AMPK. Its effects on protein synthesis and stress response pathways were more complex and dependent on exposure time. We directly observed canavanine incorporation into nascent proteins by using quantitative proteomics. Although canavanine in the absence of arginine readily incorporated into polypeptides, no motif preference for such incorporation was observed. Our findings provide a strong rationale for further developing the proposed modality based on canavanine and arginine deprivation as a potential antiglioblastoma metabolic therapy independent of the blood–brain barrier.
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影响因子：
9
作者：
Honrath B;Culmsee C;Dolga AM
通讯作者：
Dolga AM
影响因子：
3
作者：
Harding, James J.;Do, Richard K.;Abou-Alfa, Ghassan K.
通讯作者：
Abou-Alfa, Ghassan K.
影响因子：
5.6
作者：
Al-Koussa, Houssam;Al-Haddad, Maria;El-Sibai, Mirvat
通讯作者：
El-Sibai, Mirvat
影响因子：
--
作者：
Hart JR;Vogt PK
通讯作者：
Vogt PK
影响因子：
7.5
作者：
Bravo-Cordero, Jose Javier;Hodgson, Louis;Condeelis, John
通讯作者：
Condeelis, John