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EnglishStrigolactones 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.
| Titolo: | Analogs of the novel phytohormone, strigolactone, trigger apoptosis and synergize with PARP inhibitors by inducing DNA damage and inhibiting DNA repair | |
| Autori Riconosciuti: | ||
| Autori: | Croglio, Michael P.; Haake, Jefferson M.; Ryan, Colin P.; Wang, Victor S.; Lapier, Jennifer; Schlarbaum, Jamie P.; Dayani, Yaron; Artuso, Emma; Prandi, Cristina; Koltai, Hinanit; Agama, Keli; Pommier, Yves; Chen, Yu; Tricoli, Lucas; Null, Jeannine R. LaRocque; Albanese, Christopher; Yarden, Ronit I. | |
| Data di pubblicazione: | 2016 | |
| 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. | |
| Volume: | 7 | |
| Fascicolo: | 12 | |
| Pagina iniziale: | 13984 | |
| Pagina finale: | 14001 | |
| Digital Object Identifier (DOI): | 10.18632/oncotarget.7414 | |
| URL: | http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=7414&path%5B%5D=21307 | |
| Parole Chiave: | Homology-directed repair; PARP inhibitors; RAD51; Small molecule; Strigolactone; Oncology | |
| Rivista: | ONCOTARGET | |
| Appare nelle tipologie: | 03A-Articolo su Rivista |
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| File | Descrizione | Tipologia | Licenza | |
|---|---|---|---|---|
| Croglio-2016-Analogs of the novel phytohormone.pdf | articolo principale | PDF EDITORIALE | Open Access Visualizza/Apri |
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