title: Exosome-Mediated Telomere Instability in Human Breast Epithelial Cancer Cells after X Irradiation.
abstract: In directly irradiating cells, telomere metabolism is altered and similar effects have been observed in nontargeted cells. Exosomes and their cargo play dominant roles in communicating radiation-induced bystander effects with end points related to DNA damage. Here we report novel evidence that exosomes are also responsible for inducing telomere-related bystander effects. Breast epithelial cancer cells were exposed to either 2 Gy X rays, or exposed to irradiated cell conditioned media (ICCM), or exosomes purified from ICCM. Compared to control cells, telomerase activity decreased in the 2 Gy irradiated cells and both bystander samples after one population doubling. At the first population doubling, telomere length was shorter in the 2 Gy irradiated sample but not in the bystander samples. By 24 population doublings telomerase activity recovered to control levels in all samples; however, the 2 Gy irradiated sample continued to demonstrate short telomeres and both bystander samples acquired shorter telomeres. RNase treatment of exosomes prevented the bystander effects on telomerase and telomere length that were observed at 1 population doubling and 24 population doublings, respectively. Thermal denaturation by boiling eliminated the reduction of telomere length in bystander samples, suggesting that the protein fraction of exosomes also contributes to the telomeric effect. RNase treatment plus boiling abrogated all telomere-related effects in directly irradiated and bystander cell populations. These findings suggest that both proteins and RNAs of exosomes can induce alterations in telomeric metabolism, which can instigate genomic instability in epithelial cancer cells after X-ray irradiation.
authors.affiliation: a   Genomic Instability Group, Oxford Brookes University, Gipsy Lane Campus, Headington, Oxford OX3 0BP, United Kingdom.
authors.forename: Ammar H J
authors.initials: AH
authors.lastname: Al-Mayah
authors.affiliation: a   Genomic Instability Group, Oxford Brookes University, Gipsy Lane Campus, Headington, Oxford OX3 0BP, United Kingdom.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bright
authors.affiliation: a   Genomic Instability Group, Oxford Brookes University, Gipsy Lane Campus, Headington, Oxford OX3 0BP, United Kingdom.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Bowler
authors.affiliation: b   Department of Life Sciences, College of Health and Life Sciences, Brunel University, London UB8 3PH, United Kingdom.
authors.forename: Predrag
authors.initials: P
authors.lastname: Slijepcevic
authors.affiliation: c   The New Mexico Consortium, Los Alamos, New Mexico 87544.
authors.forename: Edwin
authors.initials: E
authors.lastname: Goodwin
authors.affiliation: a   Genomic Instability Group, Oxford Brookes University, Gipsy Lane Campus, Headington, Oxford OX3 0BP, United Kingdom.
authors.forename: Munira A
authors.initials: MA
authors.lastname: Kadhim
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D024201:Bystander Effect / Q000528:radiation effects; D055354:Exosomes / Q000235:genetics* / Q000528:radiation effects*; D042822:Genomic Instability / Q000528:radiation effects*; D006801:Humans; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000473:pathology*; D016615:Telomere / Q000235:genetics* / Q000528:radiation effects*; D013997:Time Factors; D014965:X-Rays / Q000009:adverse effects