ADO/hypotaurine: a novel metabolic pathway contributing to glioblastoma development.
ADO/hypotaurine: a novel metabolic pathway contributing to glioblastoma development.
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ADO/亚牛磺酸：促进胶质母细胞瘤发展的新代谢途径
DOI：
10.1038/s41420-020-00398-5
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发表时间：
2021-01-22
影响因子：
7
通讯作者：
Wang R
中科院分区：
文献类型：
--
作者：
Shen D;Tian L;Yang F;Li J;Li X;Yao Y;Lam EW;Gao P;Jin B;Wang R
通过全球代谢组学分析，在了解胶质母细胞瘤代谢方面取得了重大进展。然而，迄今为止，很少有人知道的作用，改变代谢发挥驱动侵袭性胶质瘤表型。我们以前已经确定亚牛磺酸是区分低级别和高级别肿瘤的顶级代谢物之一，并且肿瘤内亚牛磺酸水平与其生物合成酶半胱胺（2-氨基乙烷）双加氧酶（ADO）的表达之间也存在强烈关联。使用转录谱，我们进一步发现ADO/亚牛磺酸轴通过激活NF-κB通路靶向CCL 20分泌，以驱动胶质瘤“癌症干细胞”或胶质瘤癌症干细胞样细胞的自我更新和维持。相反，使用CRISPR/Cas9介导的基因编辑废除ADO/亚牛磺酸轴限制了胶质母细胞瘤细胞的体外增殖和自我更新以及原位小鼠模型中的体内肿瘤生长，表明该代谢途径是潜在的关键治疗靶点。总的来说，我们的研究结果揭示了一种可靶向的代谢途径，它有助于侵袭性高级别胶质瘤的生长和进展，以及胶质母细胞瘤诊断和治疗的一种新的预测标志物。
Significant advance has been made towards understanding glioblastoma metabolism through global metabolomic profiling. However, hitherto little is known about the role by which altered metabolism plays in driving the aggressive glioma phenotype. We have previously identified hypotaurine as one of the top-ranked metabolites for differentiating low- and high-grade tumors, and that there is also a strong association between the levels of intratumoral hypotaurine and expression of its biosynthetic enzyme, cysteamine (2-aminoethanethiol) dioxygenase (ADO). Using transcription profiling, we further uncovered that the ADO/hypotaurine axis targets CCL20 secretion through activating the NF-κB pathway to drive the self-renewal and maintenance of glioma ‘cancer stem cells’ or glioma cancer stem-like cells. Conversely, abrogating the ADO/hypotaurine axis using CRISPR/Cas9-mediated gene editing limited glioblastoma cell proliferation and self-renewal in vitro and tumor growth in vivo in an orthotopical mouse model, indicating that this metabolic pathway is a potential key therapeutic target. Collectively, our results unveil a targetable metabolic pathway, which contributes to the growth and progression of aggressive high-grade gliomas, as well as a novel predictive marker for glioblastoma diagnosis and therapy.
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影响因子：
2.9
作者：
Gao, Peng;Ji, Min;Zhang, Yong
通讯作者：
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DOI：
10.1016/j.bbamcr.2017.02.005
发表时间：
2017-05-01
影响因子：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.6
作者：
Pandey R;Caflisch L;Lodi A;Brenner AJ;Tiziani S
通讯作者：
Tiziani S