eIF4E-phosphorylation-mediated Sox2 upregulation promotes pancreatic tumor cell repopulation after irradiation
eIF4E-phosphorylation-mediated Sox2 upregulation promotes pancreatic tumor cell repopulation after irradiation
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eIF4E 磷酸化介导的 Sox2 上调促进照射后胰腺肿瘤细胞的增殖
DOI：
10.1016/j.canlet.2016.02.052
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发表时间：
2016-05-28
期刊：
影响因子：
9.7
通讯作者：
Huang, Qian
中科院分区：
文献类型：
--
作者：
Yu, Yang;Tian, Ling;Huang, Qian
胰腺癌是一种破坏性疾病，具有耐药、复发率高等特点。接受放射治疗的存活肿瘤细胞的再繁殖是复发的最常见原因之一。我们以前的研究发现了一种新的辐射后再增殖机制，即辐射后肿瘤细胞中caspase-3的激活激活了PKC Delta/p38轴，以传递促进存活肿瘤细胞再增殖的增殖信号。在这里，我们发现SOX2在照射后的胰腺癌细胞中表达上调，这在照射后肿瘤细胞的再生长中发挥了重要作用。SOX2的过表达通过旁分泌方式增强了照射后死亡的肿瘤细胞对活肿瘤细胞的生长刺激作用。此外，我们发现激活的eIF4E被MNK1磷酸化，是照射后Sox2表达的调节因子，CGP57380和利巴韦林对eIF4E的药物抑制显著减弱了Sox2介导的肿瘤细胞再增殖。最后，我们发现caspase3/PKC Delta/p38/MNK1信号通路在照射后的胰腺癌细胞中被激活。总之，我们发现了一个调节Sox2表达的新途径，Sox2可能是一个有希望的靶点，可以减少由于放疗后存活的肿瘤细胞重新聚集而导致的复发。(C)2016爱思唯尔爱尔兰有限公司。保留所有权利。
Pancreatic cancer is a devastating disease characterized by treatment resistance and high recurrence rate. Repopulation of surviving tumor cells undergoing radiotherapy is one of the most common reasons for recurrence. Our previous studies have discovered a novel mechanism for repopulation after irradiation that activation of caspase-3 in irradiated tumor cells activates PKC delta/p38 axis to transmit proliferation signals promoting repopulation of surviving tumor cells. Here we found Sox2 expression is up regulated in irradiated pancreatic cancer cells, which played a major role in tumor cell repopulation after irradiation. Over-expression of Sox2 strongly enhanced the growth-stimulating effect of irradiated dying tumor cells on living tumor cells through a paracrine modality. Furthermore, we identified activated eIF4E, which is phosphorylated by MNK1, as a regulator of Sox2 expression after irradiation, and pharmacologic inhibition of eIF4E with CGP57380 and Ribavirin significantly weakened Sox2-mediated tumor cell repopulation. Finally, we showed the activation of caspase 3/PKC delta/p38/MNK1 signal pathway in irradiated pancreatic tumor cells. Together, we showed a novel pathway regulating Sox2 expression and Sox2 may be a promising target to reduce recurrence due to repopulation of surviving tumor cells after radiotherapy. (C) 2016 Elsevier Ireland Ltd. All rights reserved.