PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways.
PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways.
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DOI：
10.1038/cddis.2014.415
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发表时间：
2014-10-02
影响因子：
9
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中科院分区：
文献类型：
--
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PI3K/Akt/mTOR通路在肿瘤转移和放疗中起核心作用。为了开发有效的治疗方法以提高放射敏感性，需要了解所涉及的放射耐药可能途径以及PI3K/Akt/mTOR抑制剂联合放疗对前列腺癌（CaP）放射耐药细胞的影响。我们发现，与亲本CaP细胞相比，CaP耐辐射细胞表现出G0/G1期和S期阻滞，细胞周期检查点、自噬和DNA修复途径蛋白激活，凋亡蛋白失活。我们还证明，与单一PI3K或mTOR抑制剂（BKM120或雷帕霉素）联合放疗相比，低剂量双PI3K/mTOR抑制剂（BEZ235或PI103）联合放疗通过抑制集落形成，诱导更多的凋亡，导致G2/M期停滞，增加双链断裂水平和减少细胞周期检查点的失活，大大提高了治疗效果。自噬和非同源末端连接(NHEJ)/同源重组（HR）修复途径蛋白在cap辐射抗性细胞中的作用。本研究描述了与CaP耐药相关的可能途径，并证明了在联合治疗中CaP耐药细胞的放射增敏效应的假定机制。本研究结果表明，PI3K/Akt/mTOR双抑制剂（BEZ235或PI103）联合放疗是治疗CaP克服放射耐药的一种有希望的方式。
The PI3K/Akt/mTOR pathway has a central role in cancer metastasis and radiotherapy. To develop effective therapeutics to improve radiosensitivity, understanding the possible pathways of radioresistance involved and the effects of a combination of the PI3K/Akt/mTOR inhibitors with radiotherapy on prostate cancer (CaP) radioresistant cells is needed. We found that compared with parent CaP cells, CaP-radioresistant cells demonstrated G0/G1 and S phase arrest, activation of cell cycle check point, autophagy and DNA repair pathway proteins, and inactivation of apoptotic proteins. We also demonstrated that compared with combination of single PI3K or mTOR inhibitors (BKM120 or Rapamycin) and radiation, low-dose of dual PI3K/mTOR inhibitors (BEZ235 or PI103) combined with radiation greatly improved treatment efficacy by repressing colony formation, inducing more apoptosis, leading to the arrest of the G2/M phase, increased double-strand break levels and less inactivation of cell cycle check point, autophagy and non-homologous end joining (NHEJ)/homologous recombination (HR) repair pathway proteins in CaP-radioresistant cells. This study describes the possible pathways associated with CaP radioresistance and demonstrates the putative mechanisms of the radiosensitization effect in CaP-resistant cells in the combination treatment. The findings from this study suggest that the combination of dual PI3K/Akt/mTOR inhibitors (BEZ235 or PI103) with radiotherapy is a promising modality for the treatment of CaP to overcome radioresistance.
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影响因子：
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