Department of Medicine, Research Institute of Biomedical Engineering, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea.
Magae Bioscience Institute, Tsukuba, Japan.
J Biochem Mol Toxicol. 2020 Oct;34(10):e22552. doi: 10.1002/jbt.22552. Epub 2020 Jun 20.
A prior study identified that 4-O-methylascochlorin (MAC), a methylated derivative of ascochlorin (ASC) from the fungus Ascochyta viciae, activates autophagy in leukemia cells by suppressing c-Myc phosphorylation. However, the effects of MAC on autophagy in other cancer cells remain unknown. In the present study, we demonstrated that MAC activated autophagy in human glioblastoma. MAC increased expression of autophagy-related proteins, such as LC3-II and Beclin-1. Moreover, MAC stimulated AMP-activated protein kinase (AMPK) phosphorylation and suppressed phosphorylation of the mTOR, p70S6K, and 4EBP1. The well-known AMPK activator metformin increased LC3-II levels, which were augmented by MAC cotreatment. AMPK knockdown decreased LC3-II levels and inhibited MAC activation of autophagy. Furthermore, MAC suppression of c-Myc expression activated autophagy. Treatment with the c-MYC inhibitor, 10058-FA, induced autophagy, as did c-Myc small interfering RNA knockdown. These effects were augmented by MAC cotreatment. Taken together, these findings indicated that MAC induces autophagy in human glioblastoma by activating AMPK signaling and inhibiting c-Myc protein expression in human glioblastoma.
先前的研究表明，真菌根壳菌素（Ascochyta viciae）中的甲基化衍生物 4-O-甲基根壳素（MAC）通过抑制 c-Myc 磷酸化来激活白血病细胞中的自噬。然而，MAC 对其他癌细胞中自噬的影响尚不清楚。在本研究中，我们证明了 MAC 可激活人神经胶质瘤中的自噬。MAC 增加了自噬相关蛋白的表达，如 LC3-II 和 Beclin-1。此外，MAC 刺激 AMP 激活蛋白激酶（AMPK）磷酸化并抑制 mTOR、p70S6K 和 4EBP1 的磷酸化。众所周知的 AMPK 激活剂二甲双胍增加了 LC3-II 水平，而 MAC 共处理则进一步增强了 LC3-II 水平。AMPK 敲低降低了 LC3-II 水平并抑制了 MAC 对自噬的激活。此外，MAC 抑制 c-Myc 表达激活了自噬。用 c-MYC 抑制剂 10058-FA 处理可诱导自噬，c-Myc 小干扰 RNA 敲低也可诱导自噬，而 MAC 共处理则进一步增强了这种作用。总之，这些发现表明，MAC 通过激活 AMPK 信号通路和抑制人神经胶质瘤中的 c-Myc 蛋白表达来诱导人神经胶质瘤中的自噬。
