title: Dynamic regulation of Rad51 by E2F1 and p53 in prostate cancer cells upon drug-induced DNA damage under hypoxia.
abstract: Intratumoral hypoxia has been proposed to create a "mutator" phenotype through downregulation of DNA repair, leading to increased genomic instability and drug resistance. Such downregulation 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 inhibitor, veliparib (2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, dihydrochloride; Abbott Laboratories, Abbott Park, IL), and the DNA-damaging topoisomerase I inhibitor camptothecin-11 (CPT-11) or SN38 (7-ethyl-10-hydroxycamptothecin) under hypoxia. Upregulation of Rad51 by E2F1 upon DNA damage under hypoxia contributed to such resistance, which was reversed by either inhibiting RAD51 transcription with small interfering RNA 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 antitumor activities were seen in the presence of Rad51 upregulation 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 of metastatic castration-resistant prostate cancers that have frequent p53 mutations and enriched genomic instability.
authors.affiliation: Department of Genitourinary Oncology and Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (M.W., X.W., J.Z.); and University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan (N.M., K.J.P.).
authors.forename: Minghui
authors.initials: M
authors.lastname: Wu
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.forename: Natalie
authors.initials: N
authors.lastname: McGregor
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Jingsong
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004249:DNA Damage; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000187:drug effects*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D017931:DNA Primers; D004273:DNA, Neoplasm; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C521013:veliparib; D000077146:Irinotecan; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002166:Camptothecin