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

Oncotarget
Michael P CroglioRonit I Yarden

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 ...Continue Reading

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Citations

Jan 10, 2019·Pest Management Science·Cristina Prandi, Ernesto G Occhiato
Oct 27, 2018·Journal of Pesticide Science·Mohammed Nihal HasanTadao Asami
Sep 5, 2019·Analytical Cellular Pathology (Amsterdam)·Mohammed Nihal HasanMahmoud Alhosin
Aug 8, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Valentina Dell'OsteCristina Prandi
Dec 19, 2016·Chemical Research in Toxicology·Xiufang SongYang Song

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Methods Mentioned

BETA
FACS
flow cytometry
chromosomal aberrations
electrophoresis
transfection
ubiquitination
protease dissociation
Immunoprecipitation
Protein Assay

Software Mentioned

Graphpad Prism
CometScore
CompuSyn
CellQuest
ImageQuant

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