Inhibition of PARP1-dependent end-joining contributes to Olaparib-mediated radiosensitization in tumor cells
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Inhibition of PARP1-dependent end-joining contributes to Olaparib-mediated radiosensitization in tumor cells. / Kötter, Annika; Cornils, Kerstin; Borgmann, Kerstin; Dahm-Daphi, Jochen; Petersen, Cordula; Dikomey, Ekkehard; Mansour Khalfallah, Wael Yassin.
In: MOL ONCOL, Vol. 8, No. 8, 01.12.2014, p. 1616-25.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Inhibition of PARP1-dependent end-joining contributes to Olaparib-mediated radiosensitization in tumor cells
AU - Kötter, Annika
AU - Cornils, Kerstin
AU - Borgmann, Kerstin
AU - Dahm-Daphi, Jochen
AU - Petersen, Cordula
AU - Dikomey, Ekkehard
AU - Mansour Khalfallah, Wael Yassin
N1 - Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - Poly-ADP-ribose-polymerase inhibitors (PARPi) are considered to be optimal tools for specifically enhancing radiosensitivity. This effect has been shown to be replication-dependent and more profound in HR-deficient tumors. Here, we present a new mode of PARPi-mediated radiosensitization which was observed in four out of six HR-proficient tumor cell lines (responders) investigated, but not in normal cells. This effect is replication-independent, as the radiosensitization remained unaffected following the inhibition of replication using aphidicolin. We showed that responders are radiosensitized by Olaparib because their DSB-repair is switched to PARP1-dependent end-joining (PARP1-EJ), as evident by (i) the significant increase in the number of residual γH2AX foci following irradiation with 3Gy and treatment with Olaparib, (ii) the enhanced enrichment of PARP1 at the chromatin after 3Gy and (iii) the inhibition of end-joining activity measured by a specific reporter substrate upon Olaparib treatment. This is the first study which directly demonstrates the switch to PARP1-EJ in tumor cells and its contribution to the response to Olaparib as a radiosensitizer, findings which could widen the scope of application of PARPi in tumor therapy.
AB - Poly-ADP-ribose-polymerase inhibitors (PARPi) are considered to be optimal tools for specifically enhancing radiosensitivity. This effect has been shown to be replication-dependent and more profound in HR-deficient tumors. Here, we present a new mode of PARPi-mediated radiosensitization which was observed in four out of six HR-proficient tumor cell lines (responders) investigated, but not in normal cells. This effect is replication-independent, as the radiosensitization remained unaffected following the inhibition of replication using aphidicolin. We showed that responders are radiosensitized by Olaparib because their DSB-repair is switched to PARP1-dependent end-joining (PARP1-EJ), as evident by (i) the significant increase in the number of residual γH2AX foci following irradiation with 3Gy and treatment with Olaparib, (ii) the enhanced enrichment of PARP1 at the chromatin after 3Gy and (iii) the inhibition of end-joining activity measured by a specific reporter substrate upon Olaparib treatment. This is the first study which directly demonstrates the switch to PARP1-EJ in tumor cells and its contribution to the response to Olaparib as a radiosensitizer, findings which could widen the scope of application of PARPi in tumor therapy.
U2 - 10.1016/j.molonc.2014.06.008
DO - 10.1016/j.molonc.2014.06.008
M3 - SCORING: Journal article
C2 - 25028150
VL - 8
SP - 1616
EP - 1625
JO - MOL ONCOL
JF - MOL ONCOL
SN - 1574-7891
IS - 8
ER -
