title: Compartmental stress responses correlate with cell survival in bystander effects induced by the DNA damage agent, bleomycin.
abstract: Physical or chemical stress applied to a cell system trigger a signal cascade that is transmitted to the neighboring cell population in a process known as bystander effect. Despite its wide occurrence in biological systems this phenomenon is mainly documented in cancer treatments. Thus understanding whether the bystander effect acts as an adaptive priming element for the neighboring cells or a sensitization factor is critical in designing treatment strategies. Here we characterize the bystander effects induced by bleomycin, a DNA-damaging agent, and compartmental stress responses associated with this phenomenon. Mouse fibroblasts were treated with increasing concentrations of bleomycin and assessed for DNA damage, cell death and induction of compartmental stress response (endoplasmic reticulum, mitochondrial and cytoplasmic stress). Preconditioned media were used to analyze bystander damage using the same end-points. Bleomycin induced bystander response was reflected primarily in increased DNA damage. This was dependent on the concentration of bleomycin and time of media conditioning. Interestingly, we found that ROS but not NO are involved in the transmission of the bystander effect. Consistent transcriptional down-regulation of the stress response factors tested (i.e. BiP, mtHsp60, Hsp70) occurred in the direct effect indicating that bleomycin might induce an arrest of transcription correlated with decreased survival. We observed the opposite trend in the bystander effect, with specific stress markers appearing increased and correlated with increased survival. These data shed new light on the potential role of stress pathways activation in bystander effects and their putative impact on the pro-survival pro-death balance.
authors.affiliation: Horia Hulubei National Institute of Physics and Nuclear Engineering - IFIN HH, 30 Reactorului St., P.O. Box MG-6, Magurele, Bucharest, Romania. Electronic address: dsavu@nipne.ro.
authors.forename: Diana
authors.initials: D
authors.lastname: Savu
authors.affiliation: Horia Hulubei National Institute of Physics and Nuclear Engineering - IFIN HH, 30 Reactorului St., P.O. Box MG-6, Magurele, Bucharest, Romania.
authors.forename: Ileana
authors.initials: I
authors.lastname: Petcu
authors.affiliation: Horia Hulubei National Institute of Physics and Nuclear Engineering - IFIN HH, 30 Reactorului St., P.O. Box MG-6, Magurele, Bucharest, Romania.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Temelie
authors.affiliation: Horia Hulubei National Institute of Physics and Nuclear Engineering - IFIN HH, 30 Reactorului St., P.O. Box MG-6, Magurele, Bucharest, Romania.
authors.forename: Cosmin
authors.initials: C
authors.lastname: Mustaciosu
authors.affiliation: Cell Physiology and Pharmacology Department, University of Leicester, Maurice Shock Building, University Road, Leicester LE1 9HN, UK. Electronic address: nm105@le.ac.uk.
authors.forename: Nicoleta
authors.initials: N
authors.lastname: Moisoi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology*; D024201:Bystander Effect / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival; D018834:Chaperonin 60 / Q000096:biosynthesis; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005347:Fibroblasts / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D018834:Chaperonin 60; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; D001761:Bleomycin
keywords: Bleomycin; Bystander effect; Compartmental stress response; DNA damage