Department of Radiotherapy, Huaihe Hospital of Henan University, Kaifeng 475000, China.
Department of Radiotherapy, Huaihe Hospital of Henan University, Kaifeng 475000, China.
Eur J Pharmacol. 2018 Jan 5;818:364-370. doi: 10.1016/j.ejphar.2017.11.009. Epub 2017 Nov 8.
Notch signaling pathway has been demonstrated to mediate radioresistance of several tumors. Our study aims to explore the function of Notch1/HES1 pathway in the radioresistance of colorectal cancer (CRC). The results demonstrated that expressions of Notch1 and Hes1 were up-regulated with the increasing irradiation dose. DAPT (N-[(3,5-difluorophenacetyl)acety1]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester) or si-Notch1 reduced expressions of Notch1 and Hes1, exacerbated irradiation-induced cell proliferation inhibition, and improved radiosensitivity of CRC cells. Moreover, DAPT or si-Notch1 increased radiation-induced DNA damage and attenuated radiation-triggered DNA-PK activity. Furthermore, xenograft in nude mice demonstrated that co-treated with DAPT and irradiation could inhibited tumor growth additively in vivo. Taken together, inhibition of Notch1/Hes1 signaling pathway enhances radiosensitivity of CRC cells, providing a potential therapeutic target to improve the therapeutic effect of radiotherapy for CRC patients.
Notch 信号通路已被证明可介导多种肿瘤的放射抵抗性。本研究旨在探讨 Notch1/HES1 通路在结直肠癌（CRC）放射抵抗性中的作用。结果表明，随着照射剂量的增加，Notch1 和 Hes1 的表达上调。DAPT（N-[(3,5-二氟苯乙酰基)乙酰基]-L-丙氨酰-2-苯基]甘氨酸-1,1-二甲基乙基酯）或 si-Notch1 降低了 Notch1 和 Hes1 的表达，加剧了照射诱导的细胞增殖抑制，并提高了 CRC 细胞的放射敏感性。此外，DAPT 或 si-Notch1 增加了辐射诱导的 DNA 损伤，并减弱了辐射触发的 DNA-PK 活性。此外，裸鼠异种移植实验表明，DAPT 与照射联合治疗可在体内协同抑制肿瘤生长。综上所述，抑制 Notch1/Hes1 信号通路可增强 CRC 细胞的放射敏感性，为提高 CRC 患者放射治疗的疗效提供了一个潜在的治疗靶点。
