Purinergic Signaling Is a Novel Mechanism of the Cellular Response to Ionizing Radiation

Abstract

Recent studies suggest the effect of radiation is observed not only in irradiated cells but also in adjacent non-irradiated cells (bystander effect), although the mechanism has not yet been fully revealed. This bystander effect may be caused by intercellular communication via a gap junction or by messengers released from irradiated cells, such as reactive oxygen species, nitric oxide, or cytokines. However, an unknown mechanism is also possible in the bystander effect. On the other hand, it is known that extracellular ATP, ADP, uridine 5′-triphosphate (UTP), and uridine 5′-diphosphate (UDP), which are released from cells, act as intercellular signaling molecules by activating purinergic P2X and P2Y receptors (purinergic signaling). Recently, I have suggested these extracellular nucleotides may be novel mediators of a radiation-induced bystander effect, because our recent studies indicated that purinergic signaling is involved in important cellular responses to radiation. Our data indicate that ionizing irradiation causes activation of the transient receptor potential melastatin type 2 (TRPM2) channel, and then ATP is released from cells through the anion channel or connexin43 hemichannel mediated by the activation of a P2X7 receptor. The released nucleotides activate P2Y6 and P2Y12 receptors, which are involved in the DNA damage response after irradiation. Activation of the P2Y6 receptor is also involved in radiation-induced activation of the epithelial growth factor receptorextracellular signal regulated protein kinase (EGFR-ERK)1/2 pathway and subsequent nuclear translocation of EGFR, which plays a role in DNA repair. Further, the induction of an antioxidant after irradiation is also mediated by the activation of the P2Y receptor. In conclusion, purinergic signaling could play an important role in the protective cellular response to ionizing irradiation.

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

“…Immune and apoptotic cells release ATP through connexin and pannexin hemichannels during inflammatory responses and uncontrolled release of intracellular ATP pools can also occur during cell necrosis (Eltzschig et al, 2006;Chekeni et al, 2010). Mounting evidence also suggests that connexin 43-mediated ATP release from γ-irradiated cells causes the radiation-induced bystander effect where adjacent, non-irradiated cells exhibit physiological responses mediated by P2 receptors Ohshima et al, 2012;Tsukimoto, 2015;Kojima et al, 2017). Interestingly, the ionotropic P2X7 receptor also has been shown to mediate ATP release (Suadicani et al, 2006;Ohshima et al, 2010), likely through its sustained activation that leads to membrane depolarization and pore formation (Dahlquist et al, 1974;Weisman et al, 1984;Buisman et al, 1988), and P2X7R blockade has been shown to attenuate ionizing radiation (IR)-induced ATP release from salivary acinar cells (Gilman et al, 2019).…”

Radiosensitizing Effect of P2X7 Receptor Antagonist on Melanoma <i>in Vitro</i> and <i>in Vivo</i>

“…Recently, the bystander effect has been reported as a novel mechanism of radiation-induced biological activity. 2) This effect is mediated by soluble factors released from cells in response to radiation, such as ROS, nitric oxide or cytokines. 2) We have also shown that irradiated cells release nucleotides, such as ATP, ADP, uridine 5′-triphosphate (UTP) or uridine 5′-diphosphate (UDP), 3,4) and that release of these nucleotides into the extracellular environment mediates cellular responses to ionizing irradiation via activation of P2 receptors.…”

“…2) This effect is mediated by soluble factors released from cells in response to radiation, such as ROS, nitric oxide or cytokines. 2) We have also shown that irradiated cells release nucleotides, such as ATP, ADP, uridine 5′-triphosphate (UTP) or uridine 5′-diphosphate (UDP), 3,4) and that release of these nucleotides into the extracellular environment mediates cellular responses to ionizing irradiation via activation of P2 receptors. 3,5) Extracellular nucleotides (ATP, ADP, UTP, and UDP) are well known as intercellular signaling molecules.…”

A Novel Mechanism of γ-Irradiation-Induced IL-6 Production Mediated by P2Y11 Receptor in Epidermal Keratinocytes

“…Involvement of P2Y11 Receptors in IL-6 Production in Response to γ-Irradiation It has been reported that ATP is released after γ-irradiation of cells, 39) and therefore we focused here on the P2 receptors. Expression of P2X3, 4, 5, 6, P2Y1, 4, 6, 11, 12, 14 was confirmed in HaCaT cells (Fig.…”

“…However, further research is needed to confirm this. The pannexin hemichannel, connexin hemichannel, maxi anion channel, vesicular nucleotide transporter (VNUT) and other anion channel are usually involved in the ATP release pathway, but involvement of an anion channel or a hemichannel has been reported in radiation-induced ATP release, 39) and maxi-anion channel is involved in the case of HaCaT cells. 25) Therefore, ATP release from HaCaT cells may be involved in γ-irradiation-induced IL-6 production.…”