APPL proteins modulate DNA repair and radiation survival of pancreatic carcinoma cells by regulating ATM.
APPL proteins modulate DNA repair and radiation survival of pancreatic carcinoma cells by regulating ATM.
复制标题
DOI：
10.1038/cddis.2014.167
复制
发表时间：
2014-04-24
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管有强化的多模式治疗，胰腺导管腺癌患者的总体生存率仍然很低。该肿瘤实体的化疗和放射抗性机制仍有待确定，以开发新的治疗策略。在癌症中，内吞作用和膜运输蛋白被利用，并且它们还关键地调节基本细胞功能，如存活和增殖。在此基础上，我们评估了含有pleckstrin同源结构域、磷酸酪氨酸结合结构域和亮氨酸拉链基序（APPL）1和2的内体蛋白衔接蛋白在胰腺癌细胞辐射抗性中的作用。在这里，我们表明，APPL 2在胰腺癌细胞中的表达上调照射后，小干扰RNA（siRNA）的APPL蛋白的消耗显着降低辐射存活平行损害DNA双链断裂（DSB）修复。此外，APPL敲低减少了共济失调毛细血管扩张突变（ATM）的放射性过度磷酸化。活化的ATM和APPL 1也显示出在照射后相互作用，这表明APPL在ATM的磷酸化中具有更直接的作用。APPL蛋白和ATM的双重靶向引起类似的放射增敏和伴随的DSB修复扰动后观察到的单一蛋白耗尽，表明ATM是APPL介导的辐射敏感性和DNA修复的作用的中央调制器。这些数据有力地表明，内体APPL蛋白有助于DNA损伤反应。靶向APPL蛋白是否有利于胰腺癌患者的生存仍有待阐明。
Despite intensive multimodal therapies, the overall survival rate of patients with ductal adenocarcinoma of the pancreas is still poor. The chemo- and radioresistance mechanisms of this tumor entity remain to be determined in order to develop novel treatment strategies. In cancer, endocytosis and membrane trafficking proteins are known to be utilized and they also critically regulate essential cell functions like survival and proliferation. On the basis of these data, we evaluated the role of the endosomal proteins adaptor proteins containing pleckstrin homology domain, phosphotyrosine binding domain and a leucine zipper motif (APPL)1 and 2 for the radioresistance of pancreatic carcinoma cells. Here, we show that APPL2 expression in pancreatic cancer cells is upregulated after irradiation and that depletion of APPL proteins by small interfering RNA (siRNA) significantly reduced radiation survival in parallel to impairing DNA double strand break (DSB) repair. In addition, APPL knockdown diminished radiogenic hyperphosphorylation of ataxia telangiectasia mutated (ATM). Activated ATM and APPL1 were also shown to interact after irradiation, suggesting that APPL has a more direct role in the phosphorylation of ATM. Double targeting of APPL proteins and ATM caused similar radiosensitization and concomitant DSB repair perturbation to that observed after depletion of single proteins, indicating that ATM is the central modulator of APPL-mediated effects on radiosensitivity and DNA repair. These data strongly suggest that endosomal APPL proteins contribute to the DNA damage response. Whether targeting of APPL proteins is beneficial for the survival of patients with pancreatic adenocarcinoma remains to be elucidated.
登录
查看更多内容
影响因子：
4
作者：
Hupalowska A;Pyrzynska B;Miaczynska M
通讯作者：
Miaczynska M
HDAC抑制剂诱导肿瘤 - 细胞选择性促凋亡转录反应。
影响因子：
9
作者：
通讯作者：
--
影响因子：
5.7
作者：
Hehlgans, Stephanie;Eke, Iris;Cordes, Nils
通讯作者：
Cordes, Nils
PKB/Akt 通过电离辐射后上调 Mre11 表达促进癌细胞中的 DSB 修复
影响因子：
8
作者：
Deng, R.;Tang, J.;Zhu, X-F
通讯作者：
Zhu, X-F
影响因子：
8
作者：
Chaturvedi, P;Eng, WK;Zhou, BBS
通讯作者：
Zhou, BBS