Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors.
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.
Efimova
Elena V
EV
Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois 60637, USA.
Mauceri
Helena J
HJ
Golden
Daniel W
DW
Labay
Edwardine
E
Bindokas
Vytautas P
VP
Darga
Thomas E
TE
Chakraborty
Chaitali
C
Barreto-Andrade
Juan Camilo
JC
Crawley
Clayton
C
Sutton
Harold G
HG
Kron
Stephen J
SJ
Weichselbaum
Ralph R
RR
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
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