Analogs of the novel phytohormone, strigolactone, trigger apoptosis and synergize with PARP inhibitors by inducing DNA damage and inhibiting DNA repair

// Michael P. Croglio 1,* , Jefferson M. Haake 1,* , Colin P. Ryan 1 , Victor S. Wang 1 , Jennifer Lapier 1 , Jamie P. Schlarbaum 1 , Yaron Dayani 1 , Emma Artuso 3 , Cristina Prandi 3 , Hinanit Koltai 4 , Keli Agama 5 , Yves Pommier 5 , Yu Chen 6 , Lucas Tricoli 2 , Jeannine R. LaRocque 1 , Christopher Albanese 2,7 and Ronit I. Yarden 1,2 1 Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA 2 The Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NW, Washington DC, USA 3 Department of Chemistry, University of Turin, Turin, Italy 4 Institute of Plant Sciences, ARO, Volcani Center, Bet Dagan, Israel 5 Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA 6 Memorial Sloan Kettering Cancer Center, New York, NY, USA 7 Department of Pathology, Georgetown University Medical Center, Washington DC, USA * These authors have contributed equally to this work Correspondence to: Ronit I. Yarden, email: // Keywords : strigolactone, small molecule, homology-directed repair, RAD51, PARP inhibitors Received : December 30, 2015 Accepted : January 16, 2016 Published : February 16, 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.