title: Analogs of the novel phytohormone, strigolactone, trigger apoptosis and synergize with PARP inhibitors by inducing DNA damage and inhibiting DNA repair.
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.
authors.affiliation: Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Croglio
authors.affiliation: Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
authors.forename: Jefferson M
authors.initials: JM
authors.lastname: Haake
authors.affiliation: Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
authors.forename: Colin P
authors.initials: CP
authors.lastname: Ryan
authors.affiliation: Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Wang
authors.affiliation: Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lapier
authors.affiliation: Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
authors.forename: Jamie P
authors.initials: JP
authors.lastname: Schlarbaum
authors.affiliation: Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Dayani
authors.affiliation: Department of Chemistry, University of Turin, Turin, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Artuso
authors.affiliation: Department of Chemistry, University of Turin, Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Prandi
authors.affiliation: Institute of Plant Sciences, ARO, Volcani Center, Bet Dagan, Israel.
authors.forename: Hinanit
authors.initials: H
authors.lastname: Koltai
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Keli
authors.initials: K
authors.lastname: Agama
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: The Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NW, Washington DC, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Tricoli
authors.affiliation: Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
authors.forename: Jeannine R
authors.initials: JR
authors.lastname: LaRocque
authors.affiliation: The Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NW, Washington DC, USA.|Department of Pathology, Georgetown University Medical Center, NW, Washington DC, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Albanese
authors.affiliation: Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.|The Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NW, Washington DC, USA.
authors.forename: Ronit I
authors.initials: RI
authors.lastname: Yarden
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010766:Phosphorylation; D010937:Plant Growth Regulators / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D007783:Lactones; D010937:Plant Growth Regulators; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C000622056:triazolide strigolactone
keywords: PARP inhibitors; RAD51; homology-directed repair; small molecule; strigolactone