Reactive oxygen species activation of MAPK pathway results in VEGF upregulation as an undesired irradiation response
Reactive oxygen species activation of MAPK pathway results in VEGF upregulation as an undesired irradiation response
复制标题
DOI：
10.1111/jop.12056
复制
发表时间：
2013-09-01
影响因子：
3.3
通讯作者：
Brieger, Juergen
中科院分区：
文献类型：
--
作者：
Drigotas, Martynas;Affolter, Annette;Brieger, Juergen
背景：放射抵抗限制了头颈部鳞状细胞癌放射治疗的有效性。我们先前证明了放射后丝裂原活化蛋白激酶(MAPK)途径的激活和血管内皮生长因子(VEGF)的释放导致肿瘤细胞反应降低。在这里，我们研究了这一机制与辐射诱导的活性氧(ROS)的关系。方法：测定IR后细胞内ROS。我们通过将两株鳞癌细胞暴露在H_2O_2中来模拟辐射诱导的ROS，并通过Western印迹、免疫组织化学和ELISA方法评价辐射和ROS对ERK磷酸化的影响。结果：我们发现IR和H_2O_2处理后PERK水平升高，U0126可以明显抑制这种作用。免疫组织化学和ELISA法显示过氧化氢作用后细胞内血管内皮生长因子水平升高。结论：我们的研究结果表明，辐射诱导的ROS激活了MAPK通路，释放了血管内皮生长因子。众所周知，血管内皮生长因子是在细胞受压迫导致细胞保护后释放出来的，所描述的机制对治疗成功具有潜在的重要意义。
BACKGROUND: Radioresistance limits the effectiveness of radiotherapy in head and neck squamous cell carcinoma. We previously demonstrated post-radiogenic mitogen-activated protein kinase (MAPK) pathway activation and vascular endothelial growth factor (VEGF) release resulting in reduced tumor cell response. Here, we examined the association of this mechanism with the induction of reactive oxygen species (ROS) under irradiation (IR).METHODS: Intracellular ROS after IR were measured. We modeled radiation-induced ROS by exposure of two SCC lines to H2O2 and evaluated the impact of irradiation and ROS on ERK phosphorylation by Western blot, immunohistochemistry, and ELISA.RESULTS: We found elevated pERK levels after treatment with IR and H2O2, which could be distinctly suppressed by U0126. Immunohistochemistry and ELISA revealed increased intracellular VEGF levels after H2O2 application.CONCLUSIONS: Our data show that irradiation-induced ROS activate the MAPK pathway and release of VEGF. As VEGF is known to be released after cellular distress resulting in cytoprotection, the described mechanism is potentially of importance for therapy success.