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: Michael P Croglio, Jefferson M Haake, Colin P Ryan, Victor S Wang, Jennifer Lapier, Jamie P Schlarbaum, Yaron Dayani, Emma Artuso, Cristina Prandi, Hinanit Koltai, Keli Agama, Yves Pommier, Yu Chen, Lucas Tricoli, Jeannine R LaRocque, Christopher Albanese, Ronit I Yarden
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 12 Pg. 13984-4001 (Mar 22 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26910887 (Publication Type: Journal Article)

Chemical References

• Lactones
• Plant Growth Regulators
• Poly(ADP-ribose) Polymerase Inhibitors
• triazolide strigolactone

Topics

• Apoptosis (drug effects)
• Cell Proliferation
• DNA Damage (drug effects)
• DNA Repair (drug effects)
• Drug Synergism
• Drug Therapy, Combination
• Humans
• Lactones (pharmacology)
• Neoplasms (drug therapy, pathology)
• Phosphorylation
• Plant Growth Regulators (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Tumor Cells, Cultured