Interferon signaling is enhanced by ATR inhibition in glioblastoma cells irradiated with X-rays, protons or carbon ions.

Autor: Rødland GE; Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway., Temelie M; Department of Life and Environmental Physics, Horia Hulubei National Institute for R&D in Physics and Nuclear Engineering, 077125 Magurele, Romania., Eek Mariampillai A; Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway., Serban AM; Department of Life and Environmental Physics, Horia Hulubei National Institute for R&D in Physics and Nuclear Engineering, 077125 Magurele, Romania., Edin NFJ; Section for biophysics and medical physics, Department of Physics, University of Oslo, 0371 Oslo, Norway., Malinen E; Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway; Section for biophysics and medical physics, Department of Physics, University of Oslo, 0371 Oslo, Norway., Lindbergsengen L; Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway., Gilbert A; UMR6252 CIMAP, Team Applications in Radiobiology with Accelerated Ions, CEA-CNRS-ENSICAEN-Université de Caen Normandie, 14000 Caen, France., Chevalier F; UMR6252 CIMAP, Team Applications in Radiobiology with Accelerated Ions, CEA-CNRS-ENSICAEN-Université de Caen Normandie, 14000 Caen, France., Savu DI; Department of Life and Environmental Physics, Horia Hulubei National Institute for R&D in Physics and Nuclear Engineering, 077125 Magurele, Romania. Electronic address: dsavu@nipne.ro., Syljuåsen RG; Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway. Electronic address: randi.syljuasen@rr-research.no.
Jazyk: angličtina
Zdroj: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology [Radiother Oncol] 2024 Dec 13; Vol. 203, pp. 110669. Date of Electronic Publication: 2024 Dec 13.
DOI: 10.1016/j.radonc.2024.110669
Abstrakt: Background and Purpose: Interferon (IFN) signaling plays an important role in antitumor immune responses. Inhibitors of the DNA damage response, such as ATR inhibitors, can increase IFN signaling upon conventional radiotherapy with X-rays. However, it is not known whether such inhibitors also enhance IFN signaling after irradiation with high linear energy transfer (LET) particles.
Materials and Methods: Human glioblastoma U-251 and T98G cells were irradiated with X-rays, protons (LET: 4.8 and 41.9 keV/µm) and carbon ions (LET: 28 and 73 keV/µm), with and without ATR inhibitor (VE-822) or ATM inhibitor (AZD1390). DNA damage signaling and cell cycle distribution were analyzed by immunoblotting and flow cytometry, and radiosensitivity was assessed by clonogenic survival assay. IFN-β secretion was measured by ELISA, and STAT1 activation was examined by immunoblotting.
Results: High-LET protons and carbon ions caused stronger activation of the DNA damage response compared to low-LET protons and X-rays at similar radiation doses. G2 checkpoint arrest was abrogated by the ATR inhibitor and prolonged by the ATM inhibitor after all radiation types. The inhibitors increased radiosensitivity, as measured after X- and carbon ion irradiation. ATR inhibition increased IFN signaling following both low-LET and high-LET irradiation. ATM inhibition also increased IFN signaling, but to a lesser extent. Notably, both cell lines secreted significantly more IFN-β when the inhibitors were combined with high-LET compared to low-LET irradiation.
Conclusion: These findings indicate that DNA damage response inhibitors can enhance IFN signaling following X-, proton and carbon ion irradiation, with a strong positive dependency on LET.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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