Dual Targeting of Akt and mTORC1 Impairs Repair of DNA Double-Strand Breaks and Increases Radiation Sensitivity of Human Tumor Cells.
Dual Targeting of Akt and mTORC1 Impairs Repair of DNA Double-Strand Breaks and Increases Radiation Sensitivity of Human Tumor Cells.
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DOI：
10.1371/journal.pone.0154745
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Toulany M
中科院分区：
文献类型：
--
作者：
Holler M;Grottke A;Mueck K;Manes J;Jücker M;Rodemann HP;Toulany M
抑制哺乳动物雷帕霉素复合物靶蛋白1（mTORC 1）诱导Akt活化。由于Akt活性介导电离辐射诱导的DNA双链断裂（DNA-DSB）的修复，从而介导实体瘤的辐射抗性，我们研究了mTORC 1和Akt的双重靶向是否损害DNA-DSB修复并诱导放射增敏。mTORC 1抑制剂雷帕霉素联合电离辐射治疗人非小细胞肺癌细胞（H661、H460、SK-MES-1、HTB-182、A549）和乳腺癌细胞系MDA-MB-231中的放射增敏导致H661和H460细胞的放射增敏在A549细胞中仅观察到非常轻微的作用，而在SK-MES-1、HTB-182或MDA-MB-231细胞（无反应者）中未观察到作用。在应答细胞中，雷帕霉素处理不激活Akt 1磷酸化，而在非应答细胞中，雷帕霉素介导PI 3 K依赖性Akt活性。Akt抑制剂MK2206分子靶向Akt或敲低Akt 1导致雷帕霉素诱导的无应答细胞的放射增敏。与单独靶向Akt相比，mTORC 1和Akt 1双靶向通过抑制非同源末端连接修复途径，显著增加了DNA双链断裂的残留频率，并提高了辐射敏感性。总之，雷帕霉素诱导的放射增敏性缺乏与雷帕霉素介导的Akt 1激活相关。因此，mTORC 1和Akt 1的双重靶向抑制DNA-DSB的修复，导致实体瘤细胞的放射增敏。
Inhibition of mammalian target of rapamycin-complex 1 (mTORC1) induces activation of Akt. Because Akt activity mediates the repair of ionizing radiation-induced DNA double-strand breaks (DNA-DSBs) and consequently the radioresistance of solid tumors, we investigated whether dual targeting of mTORC1 and Akt impairs DNA-DSB repair and induces radiosensitization. Combining mTORC1 inhibitor rapamycin with ionizing radiation in human non-small cell lung cancer (NSCLC) cells (H661, H460, SK-MES-1, HTB-182, A549) and in the breast cancer cell line MDA-MB-231 resulted in radiosensitization of H661 and H460 cells (responders), whereas only a very slight effect was observed in A549 cells, and no effect was observed in SK-MES-1, HTB-182 or MDA-MB-231 cells (non-responders). In responder cells, rapamycin treatment did not activate Akt1 phosphorylation, whereas in non-responders, rapamycin mediated PI3K-dependent Akt activity. Molecular targeting of Akt by Akt inhibitor MK2206 or knockdown of Akt1 led to a rapamycin-induced radiosensitization of non-responder cells. Compared to the single targeting of Akt, the dual targeting of mTORC1 and Akt1 markedly enhanced the frequency of residual DNA-DSBs by inhibiting the non-homologous end joining repair pathway and increased radiation sensitivity. Together, lack of radiosensitization induced by rapamycin was associated with rapamycin-mediated Akt1 activation. Thus, dual targeting of mTORC1 and Akt1 inhibits repair of DNA-DSB leading to radiosensitization of solid tumor cells.