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Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway

Oncogene volume 25, pages 3638–3648 (2006)Cite this article

Abstract

A substantial number of neural stem cells (NSCs) continue to proliferate and generate neurons in the central nervous system throughout life. Ionizing radiation, an important adjuvant therapy for glioma patients, may damage NSCs and cause neuronal deficits, such as cognitive dysfunction and memory impairment. However, the precise mechanism of radiation effects on death and differentiation of NSCs remains largely unknown. Here, we found that radiation induced apoptosis in NSCs via the mitochondrial pathway, upregulating the ratio of Bax to Bcl-2 and releasing cytochrome c into the cytoplasm. Radiation also inhibited neuronal differentiation of NSCs by 50%. Of the three stress-associated mitogen-activated protein kinases (MAPKs), only c-Jun NH2-terminal kinase (JNK) was activated in NSCs after radiation. Interestingly, JNK inhibition by the specific inhibitor SP600125 rescued NSCs from apoptosis and improved neuronal differentiation. Furthermore, we examined whether radiation directly inhibits neuronal differentiation or not. Radiation did not affect the promoter activity of NeuroD, a basic helix–loop–helix transcription factor that regulates the expression of neuronal differentiation markers. Radiation induced more apoptosis in NeuroD-positive cells than NeuroD-negative cells. We concluded that radiation activates JNK and induces apoptosis, especially in neural progenitor cells, resulting in the inhibition of neurogenesis. Our findings raise the possibility that JNK inhibition has therapeutic potential in protecting NSCs from the adverse effects of radiation.

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Abbreviations

NSC:

neural stem cell

bFGF:

basic fibroblast growth factor

EGF:

epidermal growth factor

GFAP:

glial fibrillary acidic protein

CNPase:

2′-3′-cyclic nucleotide 3′-phosphodiesterase

TMRE:

tetramethylrhodamine ethyl ester

MAPK:

mitogen-activated protein kinase

JNK:

c-Jun NH2 terminal kinase

ERK:

extracellular signal-regulated kinase

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Acknowledgements

We thank Dr Ming-Jer Tsai for providing the BETA2 promoter-luciferase plasmid and Mr Donald Norwood for his help in editing the manuscript. Financial support by USPHS Grants CA088936 and CA108558 (S Kondo), a start-up fund from The University of Texas M. D. Anderson Cancer Center (S Kondo), and a generous donation from the Anthony D Bullock III Foundation (S Kondo and Y Kondo) is acknowledged.

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Authors and Affiliations

  1. Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    T Kanzawa, E Iwado, H Aoki, A Iwamaru, E F Hollingsworth, R Sawaya, S Kondo & Y Kondo

  2. The University of Texas Graduate School of Biomedical Science at Houston, Houston, TX, USA

    S Kondo

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  1. T Kanzawa
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  2. E Iwado
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Correspondence to Y Kondo.

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Kanzawa, T., Iwado, E., Aoki, H. et al. Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway. Oncogene 25, 3638–3648 (2006). https://doi.org/10.1038/sj.onc.1209414

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