Molecular mechanisms underlying the neuroprotective effect of IGF-1 in neuroblastoma cells and the pro-metastatic effect of Dph3 in murine melanoma cells

Parkinson’s disease (PD) is mainly caused by the lost of dopaminergic neurons located in the substantia nigra pars compacta (SNpc). Thus, preventing the death of dopaminergic neurons is thought to be a potential strategy to interfere with the development of PD. The involvement of IGF-1 signaling pat...

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Main Author: Wang, Lei
Other Authors: Feng Zhiwei
Format: Theses and Dissertations
Language:English
Published: 2013
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Online Access:https://hdl.handle.net/10356/54698
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-546982023-02-28T18:41:29Z Molecular mechanisms underlying the neuroprotective effect of IGF-1 in neuroblastoma cells and the pro-metastatic effect of Dph3 in murine melanoma cells Wang, Lei Feng Zhiwei School of Biological Sciences DRNTU::Science::Biological sciences::Molecular biology Parkinson’s disease (PD) is mainly caused by the lost of dopaminergic neurons located in the substantia nigra pars compacta (SNpc). Thus, preventing the death of dopaminergic neurons is thought to be a potential strategy to interfere with the development of PD. The involvement of IGF-1 signaling pathways in neuronal cell survival has been identified in many cell types, but its downstream targets are frequently cell type-specific. In the present work, we studied the effect of IGF-1 on MPP+-induced apoptosis in human dopaminergic neuroblastoma SH-EP1 cells. We found that IGF-1 effectively protects SH-EP1 cells against MPP+-induced apoptotic cell death. We further delineated the underlying molecular mechanism and showed the PI3K/AKT pathway plays a central role in IGF-mediated cell survival against MPP+ neurotoxicity, not the mitogen-activated protein kinase (MAPK)/ERK pathway. Moreover, we demonstrated that the protective effect of AKT is largely dependent on the inactivation of glycogen synthase kinase 3β (GSK-3β), since inhibition of GSK-3β by its inhibitor, BIO, could mimic the protective effect of IGF-1 on MPP+-induced cell death in SH-EP1 cells. Interestingly, the IGF-1 potentiated PI3K/AKT activity is found to negatively regulate the c-Jun N-terminal protein kinase (JNK) related apoptotic pathway and this negative regulation is further shown to be mediated by AKT-dependent GSK-3β inactivation. Thus, our findings may provide a better understanding of the neuroprotective mechanism of IGF-1 on dopaminergic neuronal cell death and could hold tremendous implication for the development of therapy to arrest the progression of PD in the future. DOCTOR OF PHILOSOPHY (SBS) 2013-07-23T08:38:05Z 2013-07-23T08:38:05Z 2013 2013 Thesis Wang, L. (2013). Molecular mechanisms underlying the neuroprotective effect of IGF-1 in neuroblastoma cells and the pro-metastatic effect of Dph3 in murine melanoma cells. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/54698 10.32657/10356/54698 en 122 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences::Molecular biology
spellingShingle DRNTU::Science::Biological sciences::Molecular biology
Wang, Lei
Molecular mechanisms underlying the neuroprotective effect of IGF-1 in neuroblastoma cells and the pro-metastatic effect of Dph3 in murine melanoma cells
description Parkinson’s disease (PD) is mainly caused by the lost of dopaminergic neurons located in the substantia nigra pars compacta (SNpc). Thus, preventing the death of dopaminergic neurons is thought to be a potential strategy to interfere with the development of PD. The involvement of IGF-1 signaling pathways in neuronal cell survival has been identified in many cell types, but its downstream targets are frequently cell type-specific. In the present work, we studied the effect of IGF-1 on MPP+-induced apoptosis in human dopaminergic neuroblastoma SH-EP1 cells. We found that IGF-1 effectively protects SH-EP1 cells against MPP+-induced apoptotic cell death. We further delineated the underlying molecular mechanism and showed the PI3K/AKT pathway plays a central role in IGF-mediated cell survival against MPP+ neurotoxicity, not the mitogen-activated protein kinase (MAPK)/ERK pathway. Moreover, we demonstrated that the protective effect of AKT is largely dependent on the inactivation of glycogen synthase kinase 3β (GSK-3β), since inhibition of GSK-3β by its inhibitor, BIO, could mimic the protective effect of IGF-1 on MPP+-induced cell death in SH-EP1 cells. Interestingly, the IGF-1 potentiated PI3K/AKT activity is found to negatively regulate the c-Jun N-terminal protein kinase (JNK) related apoptotic pathway and this negative regulation is further shown to be mediated by AKT-dependent GSK-3β inactivation. Thus, our findings may provide a better understanding of the neuroprotective mechanism of IGF-1 on dopaminergic neuronal cell death and could hold tremendous implication for the development of therapy to arrest the progression of PD in the future.
author2 Feng Zhiwei
author_facet Feng Zhiwei
Wang, Lei
format Theses and Dissertations
author Wang, Lei
author_sort Wang, Lei
title Molecular mechanisms underlying the neuroprotective effect of IGF-1 in neuroblastoma cells and the pro-metastatic effect of Dph3 in murine melanoma cells
title_short Molecular mechanisms underlying the neuroprotective effect of IGF-1 in neuroblastoma cells and the pro-metastatic effect of Dph3 in murine melanoma cells
title_full Molecular mechanisms underlying the neuroprotective effect of IGF-1 in neuroblastoma cells and the pro-metastatic effect of Dph3 in murine melanoma cells
title_fullStr Molecular mechanisms underlying the neuroprotective effect of IGF-1 in neuroblastoma cells and the pro-metastatic effect of Dph3 in murine melanoma cells
title_full_unstemmed Molecular mechanisms underlying the neuroprotective effect of IGF-1 in neuroblastoma cells and the pro-metastatic effect of Dph3 in murine melanoma cells
title_sort molecular mechanisms underlying the neuroprotective effect of igf-1 in neuroblastoma cells and the pro-metastatic effect of dph3 in murine melanoma cells
publishDate 2013
url https://hdl.handle.net/10356/54698
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