Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway.
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 NH(2)-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.
Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
T
T
Kanzawa
E
E
Iwado
H
H
Aoki
A
A
Iwamaru
E F
EF
Hollingsworth
R
R
Sawaya
S
S
Kondo
Y
Y
Kondo
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000528:radiation effects*; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000528:radiation effects; D002453:Cell Cycle / Q000528:radiation effects; D002454:Cell Differentiation / Q000528:radiation effects*; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000528:radiation effects; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000528:radiation effects; D011839:Radiation, Ionizing; D051381:Rats; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism / Q000528:radiation effects
D000873:Anthracenes; D051792:Basic Helix-Loop-Helix Proteins; D004791:Enzyme Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C494828:Bax protein, rat; C093564:Neurogenic differentiation factor 1; C432165:pyrazolanthrone