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BioMed Research International
Volume 2017 (2017), Article ID 4163839, 10 pages
https://doi.org/10.1155/2017/4163839
Research Article

Extrinsic Apoptosis Pathway Altered by Glycogen Synthase Kinase-3β Inhibitor Influences the Net Drug Effect on NSC-34 Motor Neuron-Like Cell Survival

1Department of Neurology, Seoul Medical Center, Seoul, Republic of Korea
2Department of Neurology, College of Medicine, Seoul National University, Seoul, Republic of Korea
3Department of Neurology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
4Department of Neurology, Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul, Republic of Korea
5Department of Neurology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea

Correspondence should be addressed to Yoon-Ho Hong; moc.liamg@gnohrn and Jung-Joon Sung; rk.ca.uns@tniasjj

Received 9 January 2017; Revised 30 April 2017; Accepted 11 May 2017; Published 10 September 2017

Academic Editor: Sung-Hoon Kim

Copyright © 2017 Jee-Eun Kim et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Glycogen synthase kinase-3β (GSK-3β) 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-3β 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-3β 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, p38α, and the Fas-Daxx interaction. The GSK-3β 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 p38α and Fas-Daxx interaction. Our results suggest that GSK-3β 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-3β inhibitor.