title: Microvesicles Contribute to the Bystander Effect of DNA Damage.
abstract: Genotoxic treatments elicit DNA damage response (DDR) not only in cells that are directly exposed but also in cells that are not in the field of treatment (bystander cells), a phenomenon that is commonly referred to as the bystander effect (BE). However, mechanisms underlying the BE remain elusive. We report here that etoposide and ultraviolet (UV) exposure stimulate the production of microvesicles (MVs) in DU145 prostate cancer cells. MVs isolated from UV-treated DU145 and A431 epidermoid carcinoma cells as well as etoposide-treated DU145 cells induced phosphorylation of ataxia-telangiectasia mutated (ATM) at serine 1981 (indicative of ATM activation) and phosphorylation of histone H2AX at serine 139 (γH2AX) in naïve DU145 cells. Importantly, neutralization of MVs derived from UV-treated cells with annexin V significantly reduced the MV-associated BE activities. Etoposide and UV are known to induce DDR primarily through the ATM and ATM- and Rad3-related (ATR) pathways, respectively. In this regard, MV is likely a common source for the DNA damage-induced bystander effect. However, pre-treatment of DU145 naïve cells with an ATM (KU55933) inhibitor does not affect the BE elicited by MVs isolated from etoposide-treated cells, indicating that the BE is induced upstream of ATM actions. Taken together, we provide evidence supporting that MVs are a source of the DNA damage-induced bystander effect.
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON L8N 4A6, Canada. linx36@mcmaster.ca.|Father Sean O'Sullivan Research Institute, Hamilton, ON L8N 4A6, Canada. linx36@mcmaster.ca.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada. linx36@mcmaster.ca.
authors.forename: Xiaozeng
authors.initials: X
authors.lastname: Lin
authors.affiliation: The Genetics Laboratory, Longgang District Maternity and Child Healthcare Hospital, Longgang District, Shenzhen 518116, Guangdong, China. haowei727499@163.com.
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Wei
authors.affiliation: Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada. pierrepaulmajor@gmail.com.
authors.forename: Pierre
authors.initials: P
authors.lastname: Major
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON L8N 4A6, Canada. alnedaw@mcmaster.ca.|Father Sean O'Sullivan Research Institute, Hamilton, ON L8N 4A6, Canada. alnedaw@mcmaster.ca.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada. alnedaw@mcmaster.ca.
authors.forename: Khalid
authors.initials: K
authors.lastname: Al-Nedawi
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON L8N 4A6, Canada. alsaleha@mcmaster.ca.|Father Sean O'Sullivan Research Institute, Hamilton, ON L8N 4A6, Canada. alsaleha@mcmaster.ca.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada. alsaleha@mcmaster.ca.
authors.forename: Hassan A
authors.initials: HA
authors.lastname: Al Saleh
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON L8N 4A6, Canada. damut@mcmaster.ca.|Father Sean O'Sullivan Research Institute, Hamilton, ON L8N 4A6, Canada. damut@mcmaster.ca.|The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada. damut@mcmaster.ca.
authors.forename: Damu
authors.initials: D
authors.lastname: Tang
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D024201:Bystander Effect; D045744:Cell Line, Tumor; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology*; D000067128:Extracellular Vesicles / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D010766:Phosphorylation; D015398:Signal Transduction; D014466:Ultraviolet Rays
chemical_list: C468783:H2AX protein, human; D006657:Histones; D005047:Etoposide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; ATR; DNA damage response; microvesicles; γH2AX