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

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 d...

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Autores principales: Kim, Jee-Eun, Lim, Jung Hyun, Jeon, Gye Sun, Shin, Je-Young, Ahn, Suk-Won, Kim, Seung Hyun, Lee, Kwang-Woo, Hong, Yoon-Ho, Sung, Jung-Joon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610847/
https://www.ncbi.nlm.nih.gov/pubmed/29082245
http://dx.doi.org/10.1155/2017/4163839
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author Kim, Jee-Eun
Lim, Jung Hyun
Jeon, Gye Sun
Shin, Je-Young
Ahn, Suk-Won
Kim, Seung Hyun
Lee, Kwang-Woo
Hong, Yoon-Ho
Sung, Jung-Joon
author_facet Kim, Jee-Eun
Lim, Jung Hyun
Jeon, Gye Sun
Shin, Je-Young
Ahn, Suk-Won
Kim, Seung Hyun
Lee, Kwang-Woo
Hong, Yoon-Ho
Sung, Jung-Joon
author_sort Kim, Jee-Eun
collection PubMed
description 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.
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spelling pubmed-56108472017-10-29 Extrinsic Apoptosis Pathway Altered by Glycogen Synthase Kinase-3β Inhibitor Influences the Net Drug Effect on NSC-34 Motor Neuron-Like Cell Survival Kim, Jee-Eun Lim, Jung Hyun Jeon, Gye Sun Shin, Je-Young Ahn, Suk-Won Kim, Seung Hyun Lee, Kwang-Woo Hong, Yoon-Ho Sung, Jung-Joon Biomed Res Int Research Article 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. Hindawi 2017 2017-09-10 /pmc/articles/PMC5610847/ /pubmed/29082245 http://dx.doi.org/10.1155/2017/4163839 Text en Copyright © 2017 Jee-Eun Kim et al. https://creativecommons.org/licenses/by/4.0/ 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.
spellingShingle Research Article
Kim, Jee-Eun
Lim, Jung Hyun
Jeon, Gye Sun
Shin, Je-Young
Ahn, Suk-Won
Kim, Seung Hyun
Lee, Kwang-Woo
Hong, Yoon-Ho
Sung, Jung-Joon
Extrinsic Apoptosis Pathway Altered by Glycogen Synthase Kinase-3β Inhibitor Influences the Net Drug Effect on NSC-34 Motor Neuron-Like Cell Survival
title Extrinsic Apoptosis Pathway Altered by Glycogen Synthase Kinase-3β Inhibitor Influences the Net Drug Effect on NSC-34 Motor Neuron-Like Cell Survival
title_full Extrinsic Apoptosis Pathway Altered by Glycogen Synthase Kinase-3β Inhibitor Influences the Net Drug Effect on NSC-34 Motor Neuron-Like Cell Survival
title_fullStr Extrinsic Apoptosis Pathway Altered by Glycogen Synthase Kinase-3β Inhibitor Influences the Net Drug Effect on NSC-34 Motor Neuron-Like Cell Survival
title_full_unstemmed Extrinsic Apoptosis Pathway Altered by Glycogen Synthase Kinase-3β Inhibitor Influences the Net Drug Effect on NSC-34 Motor Neuron-Like Cell Survival
title_short Extrinsic Apoptosis Pathway Altered by Glycogen Synthase Kinase-3β Inhibitor Influences the Net Drug Effect on NSC-34 Motor Neuron-Like Cell Survival
title_sort extrinsic apoptosis pathway altered by glycogen synthase kinase-3β inhibitor influences the net drug effect on nsc-34 motor neuron-like cell survival
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610847/
https://www.ncbi.nlm.nih.gov/pubmed/29082245
http://dx.doi.org/10.1155/2017/4163839
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