Bladder Cancer-Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP-Related Metabolic Reprogramming and SerRS O-GlcNAcylation in Endothelial Cells.
Bladder Cancer-Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP-Related Metabolic Reprogramming and SerRS O-GlcNAcylation in Endothelial Cells.
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DOI：
10.1002/advs.202202993
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发表时间：
2022-10
期刊：
影响因子：
15.1
通讯作者：
Gou, Xin
中科院分区：
文献类型：
--
作者：
Li, Xinyuan;Peng, Xiang;Zhang, Chunlin;Bai, Xuesong;Li, Yang;Chen, Guo;Guo, Huixia;He, Weiyang;Zhou, Xiang;Gou, Xin
关键词：
畸形的肿瘤血管网络引发营养缺乏的肿瘤微环境(TME)，TME反过来激活内皮细胞(EC)功能并刺激新生血管形成。新的证据表明，肿瘤细胞灵活的代谢适应性有助于在波动的TME中建立不同细胞亚群之间的代谢共生。在本研究中，作者提出了一种新的在营养缺乏的TME中膀胱癌(BCA)细胞和内皮细胞之间的代谢联系，其中BCA分泌的谷氨酰胺-果糖-6-磷酸氨基转移酶1(GFAT1)通过细胞外小泡(SEV)通过增加内皮细胞内氨基己糖生物合成途径的通量来重新编程葡萄糖代谢，从而增强O-GlcN酰化。此外，内皮细胞中丝氨酸101位的丝氨酰-tRNA合成酶(SerRs)O-GlcN酰化通过泛素化促进其降解，并阻止Importinα5介导的核转位。核内SerRs通过竞争性结合近端启动子的GC富集区来抑制血管内皮生长因子的转录。此外，肿瘤细胞中的GFAT1基因敲除阻断了内皮细胞中SerRS O-GlcN酰化，并在体外和体内都减弱了血管生成。然而，给予GFAT1过表达的BCA细胞衍生的SEV可以增加GFAT1基因敲除小鼠内皮细胞中的血管生成活性。综上所述，本研究提示抑制SEV介导的BCA细胞GFAT1分泌和靶向内皮细胞SerRS O-GlcN酰化可能成为BCA抗血管生成治疗的新策略。饥饿的肿瘤内微环境促进了含有谷氨酰胺-果糖-6-磷酸氨基转移酶1的膀胱癌细胞外小泡的分泌，谷氨酰胺-果糖-6-磷酸氨基转移酶1是氨基己糖生物合成途径[HBP]的关键酶，它在膀胱癌细胞和内皮细胞之间建立了代谢联系。内皮细胞中HBP流量的增加通过促进SerRS O-GlcN酰化来改善血管生成活性。
A malformed tumour vascular network provokes the nutrient‐deprived tumour microenvironment (TME), which conversely activates endothelial cell (EC) functions and stimulates neovascularization. Emerging evidence suggests that the flexible metabolic adaptability of tumour cells helps to establish a metabolic symbiosis among various cell subpopulations in the fluctuating TME. In this study, the authors propose a novel metabolic link between bladder cancer (BCa) cells and ECs in the nutrient‐scarce TME, in which BCa‐secreted glutamine‐fructose‐6‐phosphate aminotransferase 1 (GFAT1) via small extracellular vesicles (sEVs) reprograms glucose metabolism by increasing hexosamine biosynthesis pathway flux in ECs and thus enhances O‐GlcNAcylation. Moreover, seryl‐tRNA synthetase (SerRS) O‐GlcNAcylation at serine 101 in ECs promotes its degradation by ubiquitination and impeded importin α5‐mediated nuclear translocation. Intranuclear SerRS attenuates vascular endothelial growth factor transcription by competitively binding to the GC‐rich region of the proximal promotor. Additionally, GFAT1 knockout in tumour cells blocks SerRS O‐GlcNAcylation in ECs and attenuates angiogenesis both in vitro and in vivo. However, administration of GFAT1‐overexpressing BCa cells‐derived sEVs increase the angiogenetic activity in the ECs of GFAT1‐knockout mice. In summary, this study suggests that inhibiting sEV‐mediated GFAT1 secretion from BCa cells and targeting SerRS O‐GlcNAcylation in ECs may serve as novel strategies for BCa antiangiogenetic therapy. The starving intratumor microenvironment facilitates the secretion of bladder cancer (BCa)‐derived small extracellular vesicle containing glutamine‐fructose‐6‐phosphate aminotransferase 1 (a key enzyme in hexosamine biosynthesis pathway [HBP]), which forge a metabolic link between BCa cells and endothelial cells. Increased HBP flux in endothelial cells improves angiogenetic activities by enhancing SerRS O‐GlcNAcylation.
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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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