Oncotarget

Research Papers:

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

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 and Ronit I. Yarden _

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Oncotarget. 2016; 7:13984-14001. https://doi.org/10.18632/oncotarget.7414

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Abstract

Michael P. Croglio1,*, Jefferson M. Haake1,*, Colin P. Ryan1, Victor S. Wang1, Jennifer Lapier1, Jamie P. Schlarbaum1, Yaron Dayani1, Emma Artuso3, Cristina Prandi3, Hinanit Koltai4, Keli Agama5, Yves Pommier5, Yu Chen6, Lucas Tricoli2, Jeannine R. LaRocque1, Christopher Albanese2,7 and Ronit I. Yarden1,2

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.


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