Abstract
Radiotherapeutic treatment consists of targeted application of radiation beams to a tumor but exposure of surrounding healthy tissue is inevitable. In the brain, ionizing radiation induces breakdown of the blood–brain barrier by effects on brain microvascular endothelial cells. Damage from directly irradiated cells can be transferred to surrounding non-exposed bystander cells, known as the radiation-induced bystander effect. We investigated involvement of connexin channels and paracrine signaling in radiation-induced bystander DNA damage in brain microvascular endothelial cells exposed to focused X-rays. Irradiation caused DNA damage in the directly exposed area, which propagated over several millimeters in the bystander area. DNA damage was significantly reduced by the connexin channel-targeting peptide Gap26 and the Cx43 hemichannel blocker TAT-Gap19. ATP release, dye uptake, and patch clamp experiments showed that hemichannels opened within 5 min post irradiation in both irradiated and bystander areas. Bystander signaling involved cellular Ca2+ dynamics and IP3, ATP, ROS, and NO signaling, with Ca2+, IP3, and ROS as crucial propagators of DNA damage. We conclude that bystander effects are communicated by a concerted cascade involving connexin channels, and IP3/Ca2+, ATP, ROS, and NO as major contributors of regenerative signal expansion.
Highlights
Ionizing radiation, in particular X-rays, is frequently used for diagnostic and therapeutic purposes
X-ray-induced DNA damage is propagated from irradiated to non-irradiated bystander cells To investigate the role of connexin-mediated intercellular communication in radiation-induced bystander responses, we irradiated a defined area of adherent brain microvascular endothelial cells
The results demonstrate that bystander communication of DNA damage involves connexin signaling via gap junctions and hemichannels, the canonical IP3/Ca2+ signaling cascade, extracellular adenosine triphosphate (ATP), and reactive oxygen species (ROS)/nitric oxide (NO) signaling
Summary
In particular X-rays, is frequently used for diagnostic and therapeutic purposes. The precision of selectively irradiating tumor tissues is steadily increasing, radiation toxicity in healthy tissue remains a major issue affecting the potency of radiation treatment[1]. Tissue toxicity can be linked to vascular damage since microvascular endothelial cells, especially those forming the blood–brain barrier, are vulnerable to (ROS) and DNA damage, including DNA double strand breaks (DSB), and late responses leading to apoptosis and senescence, resulting in ischemia, necrosis, and tissue fibrosis in normal surrounding tissues[2]. The damage inflicted to directly irradiated cells can be propagated to unexposed surrounding cells, known as the radiationinduced bystander effect, and mimics the direct effects of ionizing radiation encompassing induction of apoptosis, micronucleus formation, DSBs, and mutations[3,4].
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