אסיף מאגר המחקר החקלאי

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

Year:

2016

Source of publication :

Authors :

Volume :

7

Co-Authors:

Croglio, M.P., Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington, DC, United States
Haake, J.M., Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington, DC, United States
Ryan, C.P., Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington, DC, United States
Wang, V.S., Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington, DC, United States
Lapier, J., Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington, DC, United States
Schlarbaum, J.P., Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington, DC, United States
Dayani, Y., Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington, DC, United States
Artuso, E., Department of Chemistry, University of Turin, Turin, Italy
Prandi, C., Department of Chemistry, University of Turin, Turin, Italy
Koltai, H., Institute of Plant Sciences, ARO, Volcani Center, Bet Dagan, Israel
Agama, K., Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
Pommier, Y., Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
Chen, Y., Memorial Sloan Kettering Cancer Center, New York, NY, United States
Tricoli, L., The Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NW, Washington, DC, United States
Jeannine R. LaRocque, Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington, DC, United States
Albanese, C., The Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NW, Washington, DC, United States, Department of Pathology, Georgetown University Medical Center, Washington, DC, United States
Yarden, R.I., Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington, DC, United States, The Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NW, Washington, DC, United States

Facilitators :

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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 ?H2AX 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 ?H2AX 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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