Analogs of the novel phytohormone, strigolactone, trigger apoptosis and synergize with PARP inhibitors by inducing DNA damage and inhibiting DNA repair.
Oncotarget
; 7(12): 13984-4001, 2016 Mar 22.
Article
en En
| MEDLINE
| ID: mdl-26910887
ABSTRACT
Strigolactones are a novel class of plant hormones produced in roots that regulate shoot and root development. We previously reported that strigolactone analogs (SLs) induce G2/M cell cycle arrest and apoptosis in a variety of human cancer cells and inhibit tumor growth of human breast cancer xenografts in mice. SLs had no significant influences on non-transformed cells. Here we report for the first time that SLs induce DNA damage in the form of DNA double-strand breaks (DSBs) and activate the DNA damage response signaling by inducing phosphorylation of ATM, ATR and DNA-PKcs and co-localization of the DNA damage signaling protein, 53BP1, with γH2AX nuclear foci. We further report that in addition to DSBs induction, SLs simultaneously impair DSBs repair, mostly homology-directed repair (HDR) and to a lesser extent non-homologous end joining (NHEJ). In response to SLs, RAD51, the homologous DSB repair protein, is ubiquitinated and targeted for proteasomal degradation and it fails to co-localize with γH2AX foci. Interestingly, SLs synergize with DNA damaging agents-based therapeutics. The combination of PARP inhibitors and SLs showed an especially potent synergy, but only in BRCA1-proficient cells. No synergy was observed between SLs and PARP inhibitors in BRCA1-deficient cells, supporting a role for SLs in HDR impairment. Together, our data suggest that SLs increase genome instability and cell death by a unique mechanism of inducing DNA damage and inhibiting DNA repair.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Reguladores del Crecimiento de las Plantas
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Daño del ADN
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Apoptosis
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Reparación del ADN
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Inhibidores de Poli(ADP-Ribosa) Polimerasas
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Lactonas
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Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Oncotarget
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos