Dynamic Regulation of Rad51 by E2F1 and p53 in Prostate Cancer Cells upon Drug Induced DNA Damage under Hypoxia

Wu, MH. etc
Molecular Pharmacology, 2014


Intra-tumoral hypoxia has been proposed to create a "mutator" phenotype through down-regulation of DNA repair, leading to increased genomic instability and drug resistance. Such down regulation of DNA repair has been proposed to sensitize hypoxic cancer cells to DNA-damaging agents and inhibitors of DNA repair. Here, we showed that prostate cancer cells with mutant p53 were resistant to the poly(ADP-ribose) polymerase (PARP) inhibitor, veliparib and the DNA-damaging topoisomerase I inhibitor: Camptothecin-11 (CPT-11) or SN38 under hypoxia. Up-regulation of Rad51 by E2F1 upon DNA damage under hypoxia contributed to such resistance, which was reversed by either inhibiting Rad51 transcription with siRNA or by expressing wild type p53 in the p53 null prostate cancer line. Accumulation of endogenous p53, but not E2F1 and suppressed Rad51 transcription was observed in prostate cancer line with wild type p53 after DNA damage under hypoxia. Combining veliparib with CPT-11 significantly enhanced DNA damage and apoptosis under both hypoxic and normoxic culture conditions. Such enhanced DNA damage and anti-tumor activities were seen in the presence of Rad51 up-regulation and confirmed in vivo with PC3 mouse xenografts. These data illustrate a dynamic regulation of Rad51 by E2F1 and p53 in prostate cancer cells' response to hypoxia and DNA damage. The veliparib and CPT-11 combination can be further explored as a treatment for metastatic castration-resistant prostate cancers that have frequent p53 mutations and enriched genomic instability.

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Journal
Molecular Pharmacology
Year
2014
Page
doi: 10.1124/mol.113.090688
Institute
Moffitt Cancer Center;