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Irradiation causes senescence, ATP release, and P2X7 receptor isoform switch in glioblastoma.

ABSTRACT: Glioblastoma (GBM) is the most lethal brain tumor in adults. Radiation, together with temozolomide is the standard treatment, but nevertheless, relapse occurs in nearly all cases. Understanding the mechanisms underlying radiation resistance may help to find more effective therapies. After radiation treatment, ATP is released into the tumor microenvironment where it binds and activates purinergic P2 receptors, mainly of the P2X7 subtype. Two main P2X7 splice variants, P2X7A and P2X7B, are expressed in most cell types, where they associate with distinct biochemical and functional responses. GBM cells widely differ for the level of P2X7 isoform expression and accordingly for sensitivity to stimulation with extracellular ATP (eATP). Irradiation causes a dramatic shift in P2X7 isoform expression, with the P2X7A isoform being down- and the P2X7B isoform up-modulated, as well as extensive cell death and overexpression of stemness and senescence markers. Treatment with P2X7 blockers during the post-irradiation recovery potentiated irradiation-dependent cytotoxicity, suggesting that P2X7B activation by eATP generated a trophic/growth-promoting stimulus. Altogether, these data show that P2X7A and B receptor isoform levels are inversely modulated during the post-irradiation recovery phase in GBM cells.

SUBMITTER: Zanoni M

PROVIDER: S-EPMC8786947 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Irradiation causes senescence, ATP release, and P2X7 receptor isoform switch in glioblastoma.

Zanoni Michele M Sarti Alba Clara AC Zamagni Alice A Cortesi Michela M Pignatta Sara S Arienti Chiara C Tebaldi Michela M Sarnelli Anna A Romeo Antonino A Bartolini Daniela D Tosatto Luigino L Adinolfi Elena E Tesei Anna A Di Virgilio Francesco F

Cell death & disease 20220124 1

Glioblastoma (GBM) is the most lethal brain tumor in adults. Radiation, together with temozolomide is the standard treatment, but nevertheless, relapse occurs in nearly all cases. Understanding the mechanisms underlying radiation resistance may help to find more effective therapies. After radiation treatment, ATP is released into the tumor microenvironment where it binds and activates purinergic P2 receptors, mainly of the P2X7 subtype. Two main P2X7 splice variants, P2X7A and P2X7B, are express ...[more]

PMID: 35075119

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Project description:ObjectiveThe pro-inflammatory cytokine interleukin-1β (IL-1β) plays a central role in host defense against infections. High systemic IL-1β levels, however, promote the pathogenesis of inflammatory disorders. Therefore, mechanisms controlling IL-1β release are of substantial clinical interest. Recently, we identified a cholinergic mechanism inhibiting the ATP-mediated IL-1β release by human monocytes via nicotinic acetylcholine receptor (nAChR) subunits α7, α9 and/or α10. We also discovered novel nAChR agonists that trigger this inhibitory function in monocytic cells without eliciting ionotropic functions at conventional nAChRs. Here, we investigate the ion flux-independent signaling pathway that links nAChR activation to the inhibition of the ATP-sensitive P2X7 receptor (P2X7R).MethodsDifferent human and murine mononuclear phagocytes were primed with lipopolysaccharide and stimulated with the P2X7R agonist BzATP in the presence or absence of nAChR agonists, endothelial NO synthase (eNOS) inhibitors, and NO donors. IL-1β was measured in cell culture supernatants. Patch-clamp and intracellular Ca2+ imaging experiments were performed on HEK cells overexpressing human P2X7R or P2X7R with point mutations at cysteine residues in the cytoplasmic C-terminal domain.ResultsThe inhibitory effect of nAChR agonists on the BzATP-induced IL-1β release was reversed in the presence of eNOS inhibitors (L-NIO, L-NAME) as well as in U937 cells after silencing of eNOS expression. In peripheral blood mononuclear leukocytes from eNOS gene-deficient mice, the inhibitory effect of nAChR agonists was absent, suggesting that nAChRs signal via eNOS to inhibit the BzATP-induced IL-1β release. Moreover, NO donors (SNAP, S-nitroso-N-acetyl-DL-penicillamine; SIN-1) inhibited the BzATP-induced IL-1β release by mononuclear phagocytes. The BzATP-induced ionotropic activity of the P2X7R was abolished in the presence of SIN-1 in both, Xenopus laevis oocytes and HEK cells over-expressing the human P2X7R. This inhibitory effect of SIN-1 was absent in HEK cells expressing P2X7R, in which C377 was mutated to alanine, indicating the importance of C377 for the regulation of the P2X7R function by protein modification.ConclusionWe provide first evidence that ion flux-independent, metabotropic signaling of monocytic nAChRs involves eNOS activation and P2X7R modification, resulting in an inhibition of ATP signaling and ATP-mediated IL-1β release. This signaling pathway might be an interesting target for the treatment of inflammatory disorders.

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Irradiation causes senescence, ATP release, and P2X7 receptor isoform switch in glioblastoma.

Publications

Irradiation causes senescence, ATP release, and P2X7 receptor isoform switch in glioblastoma.

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