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.

DNA Injury and Repair Systems

“…Annexin V, which neutralizes the formation of MVs derived from UV-treated cells, significantly reduced the MV-associated BE activities. The presented results provide evidence supporting that MVs are a source of the DNA damage-induced bystander effect [ 13 ].…”

The Bystander Effect of Ultraviolet Radiation and Mediators

“…However, pretreatment of DU145 naive cells with an ATM (KU55933) inhibitor does not affect the bystander effect of isolated MVs from etoposide treated cells. This study shows that MVs are one of the bystander effect sources [14].…”

Long-Term Cardiac Damage Associated With Abdominal Irradiation in Mice

“…It could be the bystander effect of radiotherapy, that is, the same effect of radiotherapy on cells, tissues or organs in non-irradiated areas ( Wang et al, 2015 ; Fu et al, 2020 ). After irradiation, cells in the irradiated area can secrete cytokines, small molecular metabolites, exosomes or microvesicles containing various substances, and other media ( Lin et al, 2017 ; Ariyoshi et al, 2019 ; Ni et al, 2020 ; Mukherjee et al, 2021 ), resulting in metabolic disorders, apoptosis, endoplasmic reticulum and golgi dysfunction of cells in non-irradiated areas ( Yakovlev, 2015 ; Jella et al, 2018 ; Mladenov et al, 2018 ; Dong et al, 2020 ; Heeran et al, 2021 ; Yang et al, 2021 ). Earlier studies reported elevated levels of CRP in circulating blood, and splenic cells exhibited enhanced levels of oxidative stress and increased apoptosis after cranial irradiation in rats ( El-Din et al, 2017 ).…”