Kinomic profiling approach identifies Trk as a novel radiation modulator
Kinomic profiling approach identifies Trk as a novel radiation modulator
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DOI：
10.1016/j.radonc.2012.03.014
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发表时间：
2012-06-01
影响因子：
5.7
通讯作者：
Willey, Christopher D.
中科院分区：
文献类型：
--
作者：
Jarboe, John S.;Jaboin, Jerry J.;Willey, Christopher D.
背景资料：电离辐射治疗中使用的所有癌症患者的一半以上，因此确定的反应或阻力的机制是至关重要的发展新的治疗approaches.Materials和Methods：在这份报告中，我们利用高含量的肽阵列平台，进行多重激酶检测与实时动力学读数，以探讨血管内皮细胞的辐射反应的机制。我们将该技术应用于照射的人脐静脉内皮细胞（HUVEC）。结果：我们鉴定了49种特异性酪氨酸磷酸肽，它们在1 h的时间过程中受到照射的不同影响。在一个实施例中，原肌球蛋白受体激酶（Trk）家族成员TrkA和TrkB在照射后2至15分钟之间显示出瞬时活化。当我们使用小分子抑制剂靶向TrkA和TrkB时，HUVEC免受辐射损伤。相反，刺激TrkA使用藤黄酰胺促进辐射enhancement.Conclusions：因此，我们表明，我们的方法不仅可以识别激酶活性的快速变化，但也确定新的目标，如TrkA。TrkA抑制导致辐射保护，与增强修复辐射诱导的损伤，而TrkA刺激藤黄酰胺产生辐射敏化。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。放射治疗和肿瘤学103（2012）380-387
Background: Ionizing radiation treatment is used in over half of all cancer patients, thus determining the mechanisms of response or resistance is critical for the development of novel treatment approaches.Materials and methods: In this report, we utilize a high-content peptide array platform that performs multiplex kinase assays with real-time kinetic readout to investigate the mechanism of radiation response in vascular endothelial cells. We applied this technology to irradiated human umbilical vein endothelial cells (HUVEC).Results: We identified 49 specific tyrosine phosphopeptides that were differentially affected by irradiation over a time course of 1 h. In one example, the Tropomyosin receptor kinase (Trk) family members, TrkA and TrkB, showed transient activation between 2 and 15 min following irradiation. When we targeted TrkA and TrkB using small molecule inhibitors, HUVEC were protected from radiation damage. Conversely, stimulation of TrkA using gambogic amide promoted radiation enhancement.Conclusions: Thus, we show that our approach not only can identify rapid changes in kinase activity but also identify novel targets such as TrkA. TrkA inhibition resulted in radioprotection that correlated with enhanced repair of radiation-induced damage while TrkA stimulation by gambogic amide produced radiation sensitization. (C) 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 103 (2012) 380-387