title: Modulation of the poly (ADP-ribose) polymerase inhibitor response and DNA recombination in breast cancer cells by drugs affecting endogenous wild-type p53.
abstract: Synthetic lethal interactions between poly (ADP-ribose) polymerase (PARP) and homologous recombination (HR) repair pathways have been exploited for the development of novel mono- and combination cancer therapies. The tumor suppressor p53 was demonstrated to exhibit indirect and direct regulatory activities in DNA repair, particularly in DNA double-strand break (DSB)-induced and replication-associated HR. In this study, we tested a potential influence of the p53 status on the response to PARP inhibition, which is known to cause replication stress. Silencing endogenous or inducibly expressing p53 we found a protective effect of p53 on PARP inhibitor (PARPi)-mediated cytotoxicities. This effect was specific for wild-type versus mutant p53 and observed in cancer but not in non-transformed cell lines. Enhanced cytotoxicities after treatment with the p53-inhibitory drug Pifithrinα further supported p53-mediated resistance to PARP inhibition. Surprisingly, we equally observed increased PARPi sensitivity in the presence of the p53-activating compound Nutlin-3. As a common denominator, both drug responses correlated with decreased HR activities: Pifithrinα downregulated spontaneous HR resulting in damage accumulation. Nutlin-3 induced a decrease of DSB-induced HR, which was accompanied by a severe drop in RAD51 protein levels. Thus, we revealed a novel link between PARPi responsiveness and p53-controlled HR activities. These data expand the concept of cell and stress type-dependent healer and killer functions of wild-type p53 in response to cancer therapeutic treatment. Our findings have implications for the individualized design of cancer therapies using PARPi and the potentially combined use of p53-modulatory drugs.
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse 43, D-89075 Ulm, Germany, lisa.wiesmueller@uni-ulm.de.
authors.forename: Ivanildce Cristiane
authors.initials: IC
authors.lastname: Ireno
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse 43, D-89075 Ulm, Germany, lisa.wiesmueller@uni-ulm.de.
authors.forename: Rahel Stephanie
authors.initials: RS
authors.lastname: Wiehe
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse 43, D-89075 Ulm, Germany.
authors.forename: Andreea Iulia
authors.initials: AI
authors.lastname: Stahl
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse 43, D-89075 Ulm, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hampp
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse 43, D-89075 Ulm, Germany, Department of Toxicology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
authors.forename: Sevtap
authors.initials: S
authors.lastname: Aydin
authors.affiliation: University of North Carolina, Chapel Hill, NC 27599-7295, USA and.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.affiliation: Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm 17177, Sweden.
authors.forename: Galina
authors.initials: G
authors.lastname: Selivanova
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse 43, D-89075 Ulm, Germany, lisa.wiesmueller@uni-ulm.de.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wiesmüller
mesh_terms: D052160:Benzothiazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008970:Molecular Weight; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D059767:Recombinational DNA Repair / Q000187:drug effects*; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007546:Isoquinolines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D014050:Toluene; C095653:1,5-dihydroxyisoquinoline; C482205:nutlin 3; C121565:pifithrin; D011065:Poly(ADP-ribose) Polymerases