Department of Radiation Biology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
MSD K.K., 1-13-12 Kudankita, Chiyoda-ku, Tokyo, 102-8667, Japan.
Biochem Biophys Res Commun. 2022 Jan 29;590:82-88. doi: 10.1016/j.bbrc.2021.12.076. Epub 2021 Dec 23.
We have previously reported that severe hypoxia increases expression and activity of the DNA damage sensor ATM by activation of the key energy sensor AMPK. Here, to elucidate molecular mechanisms underlying increased expression and activity of ATM by AMPK under severe hypoxia, we investigated roles of transcriptional factors Sp1 and FoxO3a using human glioblastoma cell lines T98G and A172. Severe hypoxia increased expression of ATM, AMPKα and Sp1 but not that of FoxO3a. Knockdown of AMPKα suppressed expression of ATM and Sp1 and suppressed cellular radioresistance under severe hypoxia without affecting cell cycle distribution. Knockdown of Sp1 suppressed expression of ATM. These results suggest that increased expression and activity of AMPK under severe hypoxia induce cellular radioresistance through AMPK/Sp1/ATM pathway.
我们之前曾报道过，严重缺氧通过激活关键能量传感器 AMPK 来增加 DNA 损伤传感器 ATM 的表达和活性。在这里，为了阐明严重缺氧下 AMPK 增加 ATM 表达和活性的分子机制，我们使用人胶质母细胞瘤细胞系 T98G 和 A172 研究了转录因子 Sp1 和 FoxO3a 的作用。严重缺氧增加了 ATM、AMPKα 和 Sp1 的表达，但不增加 FoxO3a 的表达。AMPKα 的敲低抑制了严重缺氧下 ATM 和 Sp1 的表达，并抑制了细胞放射抗性，而不影响细胞周期分布。Sp1 的敲低抑制了 ATM 的表达。这些结果表明，严重缺氧下 AMPK 的表达和活性增加通过 AMPK/Sp1/ATM 途径诱导细胞放射抗性。
