Apoptosis

, Volume 19, Issue 3, pp 399–413

A role for TRAIL/TRAIL-R2 in radiation-induced apoptosis and radiation-induced bystander response of human neural stem cells

Original Paper

DOI: 10.1007/s10495-013-0925-4

Cite this article as:
Ivanov, V.N. & Hei, T.K. Apoptosis (2014) 19: 399. doi:10.1007/s10495-013-0925-4

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.

Keywords

Neural stem cells (NSC) TRAIL TRAIL-receptor Ionizing radiation Apoptosis Bystander response Neuroblastoma 

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

Supplementary material

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Supplementary material 1 (PPTX 128 kb)
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Supplementary material 2 (PPTX 485 kb)
10495_2013_925_MOESM3_ESM.pptx (186 kb)
Supplementary material 3 (PPTX 186 kb)
10495_2013_925_MOESM4_ESM.pptx (561 kb)
Supplementary material 4 (PPTX 561 kb)

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Center for Radiological Research, Department of Radiation Oncology, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA

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