Effect of JGK-263 as a new glycogen synthase kinase-3β inhibitor on extrinsic apoptosis pathway in motor neuronal cells

Gye Sun Jeon; Jee Eun Kim; Suk Won Ahn; Kyung Seok Park; Yoon Ho Hong; In Hae Ye; Ji Seon Park; Seung Hyun Kim; Kwang Woo Lee; Sung Min Kim; Jung Joon Sung

doi:10.1016/j.bbrc.2013.07.080

Effect of JGK-263 as a new glycogen synthase kinase-3β inhibitor on extrinsic apoptosis pathway in motor neuronal cells

Gye Sun Jeon, Jee Eun Kim, Suk Won Ahn, Kyung Seok Park, Yoon Ho Hong, In Hae Ye, Ji Seon Park, Seung Hyun Kim, Kwang Woo Lee, Sung Min Kim, Jung Joon Sung

Department of Neurology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Glycogen synthase kinase-3β (GSK-3β) has been identified as one of the important pathogenic mechanisms in motor neuronal death. GSK-3β inhibitor has been investigated as a modulator of apoptosis and has been shown to confer significant protective effects on cell death in neurodegenerative diseases. However, GSK-3β is known to have paradoxical effects on apoptosis subtypes, i.e., pro-apoptotic in mitochondrial-associated intrinsic apoptosis, but anti-apoptotic in death receptor-related extrinsic apoptosis. In this study, we evaluated the effect of a new GSK-3β inhibitor (JGK-263) on motor neuron cell survival and apoptosis, by using low to high doses of JGK-263 after 48. h of serum withdrawal, and monitoring changes in extrinsic apoptosis pathway components, including Fas, FasL, cleaved caspase-8, p38α, and the Fas-Daxx interaction. Cell survival peaked after treatment of serum-deprived cells with 50. μM JGK-263. The present study showed that treatment with JGK-263 reduced serum-deprivation-induced motor neuronal apoptosis by inactivating not only the intrinsic, but also the extrinsic apoptosis pathway. These results suggest that JGK-263 has a neuroprotective effect through effective modulation of the extrinsic apoptosis pathway in motor neuron degeneration.

Original language	English
Pages (from-to)	309-314
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	439
Issue number	2
DOIs	https://doi.org/10.1016/j.bbrc.2013.07.080
State	Published - 20 Sep 2013

Bibliographical note

Funding Information:
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2010-0011008 ). Additional support came in part from National Research Foundation fund ( 2010-0024351 ).

Keywords

Amyotrophic lateral sclerosis
Extrinsic apoptosis
Glycogen synthase kinase-3
JGK-263
Motor neuron

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Jeon, G. S., Kim, J. E., Ahn, S. W., Park, K. S., Hong, Y. H., Ye, I. H., Park, J. S., Kim, S. H., Lee, K. W., Kim, S. M., & Sung, J. J. (2013). Effect of JGK-263 as a new glycogen synthase kinase-3β inhibitor on extrinsic apoptosis pathway in motor neuronal cells. Biochemical and Biophysical Research Communications, 439(2), 309-314. https://doi.org/10.1016/j.bbrc.2013.07.080

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title = "Effect of JGK-263 as a new glycogen synthase kinase-3β inhibitor on extrinsic apoptosis pathway in motor neuronal cells",

abstract = "Glycogen synthase kinase-3β (GSK-3β) has been identified as one of the important pathogenic mechanisms in motor neuronal death. GSK-3β inhibitor has been investigated as a modulator of apoptosis and has been shown to confer significant protective effects on cell death in neurodegenerative diseases. However, GSK-3β is known to have paradoxical effects on apoptosis subtypes, i.e., pro-apoptotic in mitochondrial-associated intrinsic apoptosis, but anti-apoptotic in death receptor-related extrinsic apoptosis. In this study, we evaluated the effect of a new GSK-3β inhibitor (JGK-263) on motor neuron cell survival and apoptosis, by using low to high doses of JGK-263 after 48. h of serum withdrawal, and monitoring changes in extrinsic apoptosis pathway components, including Fas, FasL, cleaved caspase-8, p38α, and the Fas-Daxx interaction. Cell survival peaked after treatment of serum-deprived cells with 50. μM JGK-263. The present study showed that treatment with JGK-263 reduced serum-deprivation-induced motor neuronal apoptosis by inactivating not only the intrinsic, but also the extrinsic apoptosis pathway. These results suggest that JGK-263 has a neuroprotective effect through effective modulation of the extrinsic apoptosis pathway in motor neuron degeneration.",

keywords = "Amyotrophic lateral sclerosis, Extrinsic apoptosis, Glycogen synthase kinase-3, JGK-263, Motor neuron",

author = "Jeon, \{Gye Sun\} and Kim, \{Jee Eun\} and Ahn, \{Suk Won\} and Park, \{Kyung Seok\} and Hong, \{Yoon Ho\} and Ye, \{In Hae\} and Park, \{Ji Seon\} and Kim, \{Seung Hyun\} and Lee, \{Kwang Woo\} and Kim, \{Sung Min\} and Sung, \{Jung Joon\}",

note = "Funding Information: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2010-0011008 ). Additional support came in part from National Research Foundation fund ( 2010-0024351 ).",

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AU - Jeon, Gye Sun

AU - Kim, Jee Eun

AU - Ahn, Suk Won

AU - Park, Kyung Seok

AU - Hong, Yoon Ho

AU - Ye, In Hae

AU - Park, Ji Seon

AU - Kim, Seung Hyun

AU - Lee, Kwang Woo

AU - Kim, Sung Min

AU - Sung, Jung Joon

N1 - Funding Information: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2010-0011008 ). Additional support came in part from National Research Foundation fund ( 2010-0024351 ).

PY - 2013/9/20

Y1 - 2013/9/20

N2 - Glycogen synthase kinase-3β (GSK-3β) has been identified as one of the important pathogenic mechanisms in motor neuronal death. GSK-3β inhibitor has been investigated as a modulator of apoptosis and has been shown to confer significant protective effects on cell death in neurodegenerative diseases. However, GSK-3β is known to have paradoxical effects on apoptosis subtypes, i.e., pro-apoptotic in mitochondrial-associated intrinsic apoptosis, but anti-apoptotic in death receptor-related extrinsic apoptosis. In this study, we evaluated the effect of a new GSK-3β inhibitor (JGK-263) on motor neuron cell survival and apoptosis, by using low to high doses of JGK-263 after 48. h of serum withdrawal, and monitoring changes in extrinsic apoptosis pathway components, including Fas, FasL, cleaved caspase-8, p38α, and the Fas-Daxx interaction. Cell survival peaked after treatment of serum-deprived cells with 50. μM JGK-263. The present study showed that treatment with JGK-263 reduced serum-deprivation-induced motor neuronal apoptosis by inactivating not only the intrinsic, but also the extrinsic apoptosis pathway. These results suggest that JGK-263 has a neuroprotective effect through effective modulation of the extrinsic apoptosis pathway in motor neuron degeneration.

AB - Glycogen synthase kinase-3β (GSK-3β) has been identified as one of the important pathogenic mechanisms in motor neuronal death. GSK-3β inhibitor has been investigated as a modulator of apoptosis and has been shown to confer significant protective effects on cell death in neurodegenerative diseases. However, GSK-3β is known to have paradoxical effects on apoptosis subtypes, i.e., pro-apoptotic in mitochondrial-associated intrinsic apoptosis, but anti-apoptotic in death receptor-related extrinsic apoptosis. In this study, we evaluated the effect of a new GSK-3β inhibitor (JGK-263) on motor neuron cell survival and apoptosis, by using low to high doses of JGK-263 after 48. h of serum withdrawal, and monitoring changes in extrinsic apoptosis pathway components, including Fas, FasL, cleaved caspase-8, p38α, and the Fas-Daxx interaction. Cell survival peaked after treatment of serum-deprived cells with 50. μM JGK-263. The present study showed that treatment with JGK-263 reduced serum-deprivation-induced motor neuronal apoptosis by inactivating not only the intrinsic, but also the extrinsic apoptosis pathway. These results suggest that JGK-263 has a neuroprotective effect through effective modulation of the extrinsic apoptosis pathway in motor neuron degeneration.

KW - Amyotrophic lateral sclerosis

KW - Extrinsic apoptosis

KW - Glycogen synthase kinase-3

KW - JGK-263

KW - Motor neuron

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JF - Biochemical and Biophysical Research Communications

IS - 2

ER -

Effect of JGK-263 as a new glycogen synthase kinase-3β inhibitor on extrinsic apoptosis pathway in motor neuronal cells

Abstract

Bibliographical note

Keywords

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