Nanog Signaling Mediates Radioresistance in ALDH-Positive Breast Cancer Cells
Nanog Signaling Mediates Radioresistance in ALDH-Positive Breast Cancer Cells
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DOI：
10.3390/ijms20051151
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发表时间：
2019-03-01
影响因子：
5.6
通讯作者：
Toulany, Mahmoud
中科院分区：
文献类型：
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作者：
Harati, Mozhgan Dehghan;Rodemann, H. Peter;Toulany, Mahmoud
最近，癌症干细胞（CSCs）已被确定为化疗和放疗抵抗的主要原因。来自应用体外和体内临床前模型的实验研究的证据表明，CSC在常规治疗方案后存活。提出了几种机制参与CSC对放射治疗的抵抗。其中，与乙醛脱氢酶（ALDH）活性相关的DNA双链断裂（DSB）修复能力似乎是最突出的机制。然而，到目前为止，ALDH活性刺激DSB修复的途径尚不清楚。因此，在本研究中，我们研究了潜在的信号通路，ALDH活性刺激DSB修复，并可能导致乳腺癌细胞系在体外的辐射抗性。与ALDH阴性细胞相比，ALDH阳性细胞在辐射暴露后的细胞存活率显著提高。这种增强的细胞存活与刺激的Nanog、BMI1和Notch1蛋白表达以及刺激的Akt活性相关。通过应用过表达和敲低方法，我们清楚地证明了Nanog表达与增强的ALDH活性和细胞辐射抗性以及刺激的DSB修复相关。Akt和Notch1靶向消除Nanog介导的辐射抗性并刺激ALDH活性。总的来说，我们证明Nanog信号传导诱导肿瘤细胞的辐射抗性和刺激ALDH活性，最有可能通过激活Notch1和Akt途径。
Recently, cancer stem cells (CSCs) have been identified as the major cause of both chemotherapy and radiotherapy resistance. Evidence from experimental studies applying both in vitro and in vivo preclinical models suggests that CSCs survive after conventional therapy protocols. Several mechanisms are proposed to be involved in CSC resistance to radiotherapy. Among them, stimulated DNA double-strand break (DSB) repair capacity in association with aldehyde dehydrogenase (ALDH) activity seems to be the most prominent mechanism. However, thus far, the pathway through which ALDH activity stimulates DSB repair is not known. Therefore, in the present study, we investigated the underlying signaling pathway by which ALDH activity stimulates DSB repair and can lead to radioresistance of breast cancer cell lines in vitro. When compared with ALDH-negative cells, ALDH-positive cells presented significantly enhanced cell survival after radiation exposure. This enhanced cell survival was associated with stimulated Nanog, BMI1 and Notch1 protein expression, as well as stimulated Akt activity. By applying overexpression and knockdown approaches, we clearly demonstrated that Nanog expression is associated with enhanced ALDH activity and cellular radioresistance, as well as stimulated DSB repair. Akt and Notch1 targeting abrogated the Nanog-mediated radioresistance and stimulated ALDH activity. Overall, we demonstrate that Nanog signaling induces tumor cell radioresistance and stimulates ALDH activity, most likely through activation of the Notch1 and Akt pathways.