title: Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors.
abstract: Persistent DNA double-strand breaks (DSB) may determine the antitumor effects of ionizing radiation (IR) by inducing apoptosis, necrosis, mitotic catastrophe, or permanent growth arrest. IR induces rapid modification of megabase chromatin domains surrounding DSBs via poly-ADP-ribosylation, phosphorylation, acetylation, and protein assembly. The dynamics of these IR-induced foci (IRIF) have been implicated in DNA damage signaling and DNA repair. As an IRIF reporter, we tracked the relocalization of green fluorescent protein fused to a chromatin binding domain of the checkpoint adapter protein 53BP1 after IR of breast cancer cells and tumors. To block DSB repair in breast cancer cells and tumors, we targeted poly(ADP-ribose) polymerase (PARP) with ABT-888 (veliparib), one of several PARP inhibitors currently in clinical trials. PARP inhibition markedly enhanced IRIF persistence and increased breast cancer cell senescence both in vitro and in vivo, arguing for targeting IRIF resolution as a novel therapeutic strategy.
authors.affiliation: Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Efimova
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Mauceri
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Golden
authors.forename: Edwardine
authors.initials: E
authors.lastname: Labay
authors.forename: Vytautas P
authors.initials: VP
authors.lastname: Bindokas
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Darga
authors.forename: Chaitali
authors.initials: C
authors.lastname: Chakraborty
authors.forename: Juan Camilo
authors.initials: JC
authors.lastname: Barreto-Andrade
authors.forename: Clayton
authors.initials: C
authors.lastname: Crawley
authors.forename: Harold G
authors.initials: HG
authors.lastname: Sutton
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kron
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D048708:Cell Growth Processes / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007259:Infrared Rays; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011993:Recombinant Fusion Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C521013:veliparib; D049452:Green Fluorescent Proteins