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

作者：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; LaRocque Jeannine R; Albanese Christopher; Yarden Ronit I^*

来源：Oncotarget, 2016, 7(12): 13984-14001.

DOI：10.18632/oncotarget.7414

• strigolactone
• small molecule
• homology-directed repair
• RAD51
• PARP inhibitors

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 yH2AX 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 yH2AX 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.

• 出版日期2016-3-22