Andrea O Fontana1, Marc A Augsburger1, Nicole Grosse1, Matthias Guckenberger1, Anthony J Lomax2, Alessandro A Sartori3, Martin N Pruschy4. 1. Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Switzerland. 2. Paul Scherrer Institute, Villigen, Switzerland. 3. Institute of Molecular Cancer Research, University of Zurich, Switzerland. 4. Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Switzerland. Electronic address: martin.pruschy@usz.ch.
Abstract
BACKGROUND AND PURPOSE: Non-homologous end-joining (NHEJ) and homologous recombination (HR) contribute to the repair of irradiation-induced DNA double-strand breaks (DSBs). We investigated the impact of the two major DSB repair machineries for cellular survival of human tumor cells in response to proton- and photon-irradiation. MATERIALS AND METHODS: DNA damage repair and cell survival were analyzed in wildtype, HR- and NHEJ-repair-compromised and pharmacologically DNA-PKcs-inhibited human tumor cells in response to clinically relevant, low-linear energy transfer proton- and 200-keV photon-irradiation. RESULTS: Pharmacological inhibition of DNA-PKcs strongly radiosensitized lung adenocarcinoma and glioblastoma cells to photon- but to a much lower extent to proton-irradiation. Enhanced radiosensitization correlated with strongly delayed repair kinetics with elevated amounts of γH2AX foci after photon-irradiation. Interestingly, we observed reduced phosphorylation of DNA-PKcs at Ser-2056 and Thr-2609 clusters after proton-irradiation compared to photon-irradiation. In contrast, A549 cells depleted of the RAD51 recombinase were markedly hypersensitive to proton-irradiation in comparison with control cells. Likewise, human BRCA2-deficient ovarian carcinoma cells were hypersensitive toward proton- in comparison with photon-irradiation. CONCLUSION: A differential DNA damage response with enhanced susceptibility of HR-deficient tumor cells to proton-irradiation and increased sensitivity of photon-irradiated tumor cells to NHEJ inhibitors were demonstrated.
BACKGROUND AND PURPOSE: Non-homologous end-joining (NHEJ) and homologous recombination (HR) contribute to the repair of irradiation-induced DNA double-strand breaks (DSBs). We investigated the impact of the two major DSB repair machineries for cellular survival of humantumor cells in response to proton- and photon-irradiation. MATERIALS AND METHODS: DNA damage repair and cell survival were analyzed in wildtype, HR- and NHEJ-repair-compromised and pharmacologically DNA-PKcs-inhibited humantumor cells in response to clinically relevant, low-linear energy transfer proton- and 200-keV photon-irradiation. RESULTS: Pharmacological inhibition of DNA-PKcs strongly radiosensitized lung adenocarcinoma and glioblastoma cells to photon- but to a much lower extent to proton-irradiation. Enhanced radiosensitization correlated with strongly delayed repair kinetics with elevated amounts of γH2AX foci after photon-irradiation. Interestingly, we observed reduced phosphorylation of DNA-PKcs at Ser-2056 and Thr-2609 clusters after proton-irradiation compared to photon-irradiation. In contrast, A549 cells depleted of the RAD51 recombinase were markedly hypersensitive to proton-irradiation in comparison with control cells. Likewise, humanBRCA2-deficient ovarian carcinoma cells were hypersensitive toward proton- in comparison with photon-irradiation. CONCLUSION: A differential DNA damage response with enhanced susceptibility of HR-deficient tumor cells to proton-irradiation and increased sensitivity of photon-irradiated tumor cells to NHEJ inhibitors were demonstrated.
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