Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer
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Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer. / Mansour, W. Y.; Tennstedt, Pierre; Volquardsen, J.; Oing, C.; Kluth, M.; Hube-Magg, C.; Borgmann, K.; Simon, R.; Petersen, C.; Dikomey, E.; Rothkamm, K.
in: SCI REP-UK, Jahrgang 8, Nr. 1, 02.03.2018, S. 3947.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer
AU - Mansour, W. Y.
AU - Tennstedt, Pierre
AU - Volquardsen, J.
AU - Oing, C.
AU - Kluth, M.
AU - Hube-Magg, C.
AU - Borgmann, K.
AU - Simon, R.
AU - Petersen, C.
AU - Dikomey, E.
AU - Rothkamm, K.
PY - 2018/3/2
Y1 - 2018/3/2
N2 - Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdown. No association was observed between PTEN-status and RAD51 expression either in-vitro or in-vivo in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation. Consistently, AKT inhibition recovered the G2/M-checkpoint and restored HR efficiency in PTEN-depleted cells. We show that, although PTEN loss correlates with a worse prognosis, it may predict for improved response of PC patients to radiotherapy. Further, we provide evidence for the use of PTEN as a biomarker for predicting the response to PARP inhibitors as radiosensitizing agents in prostate cancer. Collectively, these data implicate PTEN in maintaining genomic stability by delaying G2/M-phase progression of damaged cells, thus allowing time for DSB repair by HR. Furthermore, we identify PTEN-status in PC as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor alone or combined with radiotherapy.
AB - Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdown. No association was observed between PTEN-status and RAD51 expression either in-vitro or in-vivo in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation. Consistently, AKT inhibition recovered the G2/M-checkpoint and restored HR efficiency in PTEN-depleted cells. We show that, although PTEN loss correlates with a worse prognosis, it may predict for improved response of PC patients to radiotherapy. Further, we provide evidence for the use of PTEN as a biomarker for predicting the response to PARP inhibitors as radiosensitizing agents in prostate cancer. Collectively, these data implicate PTEN in maintaining genomic stability by delaying G2/M-phase progression of damaged cells, thus allowing time for DSB repair by HR. Furthermore, we identify PTEN-status in PC as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor alone or combined with radiotherapy.
KW - Cell Division
KW - Checkpoint Kinase 1/genetics
KW - Combined Modality Therapy
KW - DNA Breaks, Double-Stranded
KW - DNA Repair
KW - G2 Phase
KW - Homologous Recombination
KW - Humans
KW - Male
KW - PTEN Phosphohydrolase/genetics
KW - Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
KW - Prostatic Neoplasms/drug therapy
KW - Treatment Outcome
U2 - 10.1038/s41598-018-22289-7
DO - 10.1038/s41598-018-22289-7
M3 - SCORING: Journal article
C2 - 29500400
VL - 8
SP - 3947
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
IS - 1
ER -