Department of Neurology, Seoul Medical Center, Seoul, Republic of Korea.
Department of Neurology, College of Medicine, Seoul National University, Seoul, Republic of Korea.
Biomed Res Int. 2017;2017:4163839. doi: 10.1155/2017/4163839. Epub 2017 Sep 10.
Glycogen synthase kinase-3 (GSK-3) inhibitors have been suggested as a core regulator of apoptosis and have been investigated as therapeutic agents for neurodegenerative diseases, including amyotrophic lateral sclerosis. However, GSK-3 has an interesting paradoxical effect of being proapoptotic during mitochondrial-mediated intrinsic apoptosis but antiapoptotic during death receptor-mediated extrinsic apoptosis. We assessed the effect of low to high doses of a GSK-3 inhibitor on survival and apoptosis of the NSC-34 motor neuron-like cell line after serum withdrawal. Then, we identified changes in extrinsic apoptosis markers, including Fas, Fas ligand, cleaved caspase-8, p38, and the Fas-Daxx interaction. The GSK-3 inhibitor had an antiapoptotic effect at the low dose but was proapoptotic at the high dose. Proapoptotic effect at the high dose can be explained by increased signals in cleaved caspase-8 and the motor neuron-specific p38 and Fas-Daxx interaction. Our results suggest that GSK-3 inhibitor dose may determine the summation effect of the intrinsic and extrinsic apoptosis pathways. The extrinsic apoptosis pathway might be another therapeutic target for developing a potential GSK-3 inhibitor.
糖原合酶激酶-3 (GSK-3) 抑制剂被认为是细胞凋亡的核心调节剂，并被研究作为治疗包括肌萎缩性侧索硬化症在内的神经退行性疾病的药物。然而，GSK-3 具有一个有趣的悖论效应，即在线粒体介导的内在凋亡过程中是促凋亡的，但在死亡受体介导的外在凋亡过程中是抗凋亡的。我们评估了低剂量到高剂量的 GSK-3 抑制剂对血清剥夺后 NSC-34 运动神经元样细胞系存活和凋亡的影响。然后，我们确定了外在凋亡标志物的变化，包括 Fas、Fas 配体、裂解的 caspase-8、p38 和 Fas-Daxx 相互作用。GSK-3 抑制剂在低剂量时具有抗凋亡作用，但在高剂量时具有促凋亡作用。高剂量时的促凋亡作用可以用裂解的 caspase-8 以及运动神经元特异性 p38 和 Fas-Daxx 相互作用的信号增加来解释。我们的结果表明，GSK-3 抑制剂的剂量可能决定内在和外在凋亡途径的总和效应。外在凋亡途径可能是开发潜在 GSK-3 抑制剂的另一个治疗靶点。
