dc.contributor.author | Ireno, Ivanildce Cristiane | |
dc.contributor.author | Wiehe, Rahel Stephanie | |
dc.contributor.author | Stahl, Andreea Iulia | |
dc.contributor.author | Hampp, Stephanie | |
dc.contributor.author | Aydin, Sevtap | |
dc.contributor.author | Troester, Melissa A. | |
dc.contributor.author | Selivanova, Galina | |
dc.contributor.author | Wiesmueller, Lisa | |
dc.date.accessioned | 2019-12-16T10:09:10Z | |
dc.date.available | 2019-12-16T10:09:10Z | |
dc.date.issued | 2014 | |
dc.identifier.issn | 0143-3334 | |
dc.identifier.uri | https://doi.org/10.1093/carcin/bgu160 | |
dc.identifier.uri | http://hdl.handle.net/11655/19870 | |
dc.description.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 Pifithrin alpha 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: Pifithrin alpha 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. | |
dc.language.iso | en | |
dc.publisher | Oxford Univ Press | |
dc.relation.isversionof | 10.1093/carcin/bgu160 | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject | Oncology | |
dc.title | Modulation Of The Poly (Adp-Ribose) Polymerase Inhibitor Response And Dna Recombination In Breast Cancer Cells By Drugs Affecting Endogenous Wild-Type P53 | |
dc.type | info:eu-repo/semantics/article | |
dc.relation.journal | Carcinogenesis | |
dc.contributor.department | Farmasötik Toksikoloji | |
dc.identifier.volume | 35 | |
dc.identifier.issue | 10 | |
dc.identifier.startpage | 2273 | |
dc.identifier.endpage | 2282 | |
dc.description.index | WoS | |
dc.description.index | Scopus | |