Abstract
Adult neurons, which are terminally differentiated cells, demonstrate substantial radioresistance. In contrast, human neural stem cells (NSC), which have a significant proliferative capacity, are highly sensitive to ionizing radiation. Cranial irradiation that is widely used for treatment of brain tumors may induce death of NSC and further cause substantial cognitive deficits such as impairing learning and memory. The main goal of our study was to determine a mechanism of NSC radiosensitivity. We observed a constitutive high-level expression of TRAIL-R2 in human NSC. On the other hand, ionizing radiation through generation of reactive oxygen species targeted cell signaling pathways and dramatically changed the pattern of gene expression, including upregulation of TRAIL. A significant increase of endogenous expression and secretion of TRAIL could induce autocrine/paracrine stimulation of the TRAIL-R2-mediated signaling cascade with activation of caspase-3-driven apoptosis. Furthermore, paracrine stimulation could initiate bystander response of non-targeted NSC that is driven by death ligands produced by directly irradiated NSC. Experiments with media transfer from directly irradiated NSC to non-targeted (bystander) NSC confirmed a role of secreted TRAIL for induction of a death signaling cascade in non-targeted NSC. Subsequently, TRAIL production through elimination of bystander TRAIL-R-positive NSC might substantially restrict a final yield of differentiating young neurons. Radiation-induced TRAIL-mediated apoptosis could be partially suppressed by anti-TRAIL antibody added to the cell media. Interestingly, direct gamma-irradiation of SK-N-SH human neuroblastoma cells using clinical doses (2–5 Gy) resulted in low levels of apoptosis in cancer cells that was accompanied however by induction of a strong bystander response in non-targeted NSC. Numerous protective mechanisms were involved in the maintenance of radioresistance of neuroblastoma cells, including constitutive PI3K-AKT over-activation and endogenous synthesis of TGFβ1. Specific blockage of these survival pathways was accompanied by a dramatic increase in radiosensitivity of neuroblastoma cells. Intercellular communication between cancer cells and NSC could potentially be involved in amplification of cancer pathology in the brain.
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Abbreviations
- FACS:
-
Fluorescence-activated cell sorter
- FGF2:
-
Fibroblast growth factor-2 (basic)
- DR5:
-
Death receptor-5 (synonym for TRAIL-R2)
- IκB:
-
Inhibitor of NF-κB
- IKK:
-
Inhibitor nuclear factor kappa B kinase
- JNK:
-
c-Jun N-terminal kinase
- MAPK:
-
Mitogen-activated protein kinase
- MEK:
-
MAPK/ERK kinase
- MEF:
-
Median fluorescence intensity
- NF-κB:
-
Nuclear factor kappa B
- NSC:
-
Neural stem cells
- PARP1:
-
Poly (ADP-ribose) polymerase-1
- PI:
-
Propidium iodide
- STAT:
-
Signal transducers and activators of transcription
- TGFβ:
-
Transforming growth factor beta
- TGFβ-R:
-
TGFβ-receptor
- TNFα:
-
Tumor necrosis factor alpha
- TRAIL:
-
TNF-related apoptosis ligand
- TRAIL-R:
-
TRAIL-receptor
- zVAD:
-
Carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone
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Acknowledgments
We would like to thank Drs. Adayabalam Balajee, Mercy Davidson, Peter Grabham and Howard Lieberman for advice, critical reading of the manuscript and discussion. This work was supported by NIH Grant P01 CA049062 and Pilot Grant of the Department of Dermatology, Columbia University (P30AR044531-11, Project GG006336).
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The authors declare that there are no conflicts of interest.
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Ivanov, V.N., Hei, T.K. A role for TRAIL/TRAIL-R2 in radiation-induced apoptosis and radiation-induced bystander response of human neural stem cells. Apoptosis 19, 399–413 (2014). https://doi.org/10.1007/s10495-013-0925-4
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DOI: https://doi.org/10.1007/s10495-013-0925-4