title: Calcium, oxidative stress and connexin channels, a harmonious orchestra directing the response to radiotherapy treatment?
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.
authors.affiliation: Department of Basic Medical Sciences - Physiology Group, Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium. Electronic address: Elke.Decrock@gmail.com.
authors.forename: Elke
authors.initials: E
authors.lastname: Decrock
authors.affiliation: Department of Basic Medical Sciences - Physiology Group, Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Delphine
authors.initials: D
authors.lastname: Hoorelbeke
authors.affiliation: Department of Basic Medical Sciences - Physiology Group, Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium; Radiobiology Unit, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN), B-2400 Mol, Belgium.
authors.forename: Raghda
authors.initials: R
authors.lastname: Ramadan
authors.affiliation: Department of Basic Medical Sciences - Physiology Group, Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium; Molecular Signalling and Cell Death Unit, VIB-UGent Center for Inflammation Research, VIB, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Tinneke
authors.initials: T
authors.lastname: Delvaeye
authors.affiliation: Department of Basic Medical Sciences - Physiology Group, Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Marijke
authors.initials: M
authors.lastname: De Bock
authors.affiliation: Department of Basic Medical Sciences - Physiology Group, Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Basic Medical Sciences - Anatomy and Embryology group, Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Krysko
authors.affiliation: Radiobiology Unit, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN), B-2400 Mol, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Baatout
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Molecular and Cellular Signalling, KU Leuven Campus Gasthuisberg, B-3000 Leuven, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
authors.affiliation: Radiobiology Unit, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN), B-2400 Mol, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Aerts
authors.affiliation: Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vinken
authors.affiliation: Department of Basic Medical Sciences - Physiology Group, Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Leybaert
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D017630:Connexins / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress; D011878:Radiotherapy; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017630:Connexins; D017382:Reactive Oxygen Species; D002118:Calcium
keywords: Bystander effect; Calcium; Connexin hemichannel; Gap junction; Ionizing radiation; Oxidative stress