Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba, 278-0022, Japan.
Division of Animal Sciences, Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, 1-2 Ohwashi, Tsukuba, Ibaraki, 305-8634, Japan.
Biochem Biophys Res Commun. 2020 Apr 16;524(4):869-875. doi: 10.1016/j.bbrc.2020.01.167. Epub 2020 Feb 10.
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neuroprotective factor produced in response to endoplasmic reticulum (ER) stress induced by various stressors, but its involvement in the radioresistance of tumor cells is unknown. Here, we found that MANF is released after γ-irradiation (2 Gy and 4 Gy) of B16 melanoma cells, and its release was suppressed by 4-phenylbutyric acid, an ER stress inhibitor. MANF was not released after low-dose (1 Gy) γ-irradiation, but pretreatment of 1 Gy-irradiated cells with recombinant MANF enhanced the cellular DNA damage response and attenuated reproductive cell death. In MANF-knockdown cells, the DNA damage response and p53 activation by γ-irradiation (2 Gy) were suppressed, and reproductive cell death was increased. MANF also activated the ERK signaling pathway. Our findings raise the possibility that MANF could be a new target for overcoming radioresistance.
中脑星形胶质细胞衍生神经营养因子（MANF）是一种在受到各种应激源诱导的内质网（ER）应激时产生的神保护因子，但它是否参与肿瘤细胞的放射抵抗性尚不清楚。在这里，我们发现 MANF 在 γ 射线（2Gy 和 4Gy）照射 B16 黑色素瘤细胞后被释放，其释放被 ER 应激抑制剂 4-苯基丁酸抑制。低剂量（1Gy）γ射线照射后不释放 MANF，但用重组 MANF 预处理 1Gy 照射的细胞增强了细胞的 DNA 损伤反应，并减弱了有丝分裂细胞死亡。在 MANF 敲低细胞中，γ射线（2Gy）照射引起的 DNA 损伤反应和 p53 激活受到抑制，有丝分裂细胞死亡增加。MANF 还激活了 ERK 信号通路。我们的研究结果提出了这样一种可能性，即 MANF 可能成为克服放射抵抗性的新靶标。
