Review
Calcium, oxidative stress and connexin channels, a harmonious orchestra directing the response to radiotherapy treatment?

https://doi.org/10.1016/j.bbamcr.2017.02.007Get rights and content
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Highlights

  • Connexin channels can provide passageways for the spread of radiation-induced effects.

  • Mitochondria involved in Ca2 + signaling and ROS production, are affected by radiation.

  • Ca2 +/ROS signaling can modulate biological effects in irradiated and bystander cells.

  • Intercellular Ca2 + waves may provide an amplification mechanism for bystander effects.

  • The Ca2 +-mobilizing agonist ATP may modulate the response to radiotherapy.

Abstract

Although radiotherapy is commonly used to treat cancer, its beneficial outcome is frequently hampered by the radiation resistance of tumor cells and adverse reactions in normal tissues. Mechanisms of cell-to-cell communication and how intercellular signals are translated into cellular responses, have become topics of intense investigation, particularly within the field of radiobiology. A substantial amount of evidence is available demonstrating that both gap junctional and paracrine communication pathways can propagate radiation-induced biological effects at the intercellular level, commonly referred to as radiation-induced bystander effects (RIBE). Multiple molecular signaling mechanisms involving oxidative stress, kinases, inflammatory molecules, and Ca2+ are postulated to contribute to RIBE. Ca2+ is a highly versatile and ubiquitous second messenger that regulates diverse cellular processes via the interaction with various signaling cascades. It furthermore provides a fast system for the dissemination of information at the intercellular level. Channels formed by transmembrane connexin (Cx) proteins, i.e. hemichannels and gap junction channels, can mediate the cell-to-cell propagation of increases in intracellular Ca2+ by ministering paracrine and direct cell-cell communication, respectively. We here review current knowledge on radiation-induced signaling mechanisms in irradiated and bystander cells, particularly focusing on the contribution of oxidative stress, Ca2+ and Cx channels. By illustrating the tight interplay between these different partners, we provide a conceptual framework for intercellular Ca2+ signaling as a key player in modulating the RIBE and the overall response to radiation.

Abbreviations

ADP
adenosine diphosphate
AMP
adenosine monophosphate
ATP
adenosine triphosphate
[Ca2+]i
intracellular calcium concentration
CaM
calmodulin
CaMKII
Ca2+/calmodulin-dependent kinase II
cAMP
cyclic adenosine monophosphate
COX-2
cyclooxygenase-2
Cx
connexin
EGFR
epidermal growth factor receptor
eNOS
endothelial nitric oxide synthase
ER
endoplasmic reticulum
ERK
extracellular signal-regulated kinase
GJC
gap junction channel
GPCR
G-protein coupled receptor
GRP75
glucose regulated protein 75
HMGB-1
high-mobility group box 1
IL
interleukin
iNOS
inducible nitric oxide synthase
IP3
inositol 1,4,5-trisphosphate
IP3R
inositol 1,4,5-trisphosphate receptor
MAPK
mitogen-activated protein kinase
mtDNA
mitochondrial DNA
mTOR
mammalian target of rapamycin
NADPH
nicotinamide adenine dinucleotide phosphate
NO
nitric oxide
nNOS
neuronal nitric oxide synthase
Panx
pannexin
PGE2
prostaglandin E2
PI3K
phosphatidylinositol 3-kinase
PKC
protein kinase C
PLC
phospholipase C
P2X7R
P2X7 receptor
RIBE
radiation-induced bystander effect
RNS
reactive nitrogen species
ROS
reactive oxygen species
RyR
ryanodine receptor
TNF-α
tumor necrosis factor-α
VDAC
voltage-dependent anion channel

Keywords

Ionizing radiation
Calcium
Oxidative stress
Connexin hemichannel
Gap junction
Bystander effect

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