Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer.
W Y MansourP TennstedtJ VolquardsenC OingM KluthC Hube-MaggK BorgmannR SimonC PetersenE DikomeyKai RothkammPublished in: Scientific reports (2018)
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.
Keyphrases
- dna damage
- cell proliferation
- pi k akt
- prostate cancer
- dna repair
- cell cycle arrest
- signaling pathway
- cell cycle
- early stage
- induced apoptosis
- oxidative stress
- radical prostatectomy
- escherichia coli
- locally advanced
- crispr cas
- machine learning
- poor prognosis
- prognostic factors
- squamous cell carcinoma
- newly diagnosed
- cell death
- long non coding rna
- dna damage response
- circulating tumor
- genome wide