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Mdm2 selectively suppresses DNA damage arising from inhibition of topoisomerase II independent of p53

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Abstract

Mdm2 is often overexpressed in tumors that retain wild-type TP53 but may affect therapeutic response independently of p53. Herein is shown that tumor cells with MDM2 amplification are selectively resistant to treatment with topoisomerase II poisons but not other DNA damaging agents. Tumor cells that overexpress Mdm2 have reduced DNA double-strand breaks in response to doxorubicin or etoposide. This latter result is not due to altered drug uptake. The selective attenuation of DNA damage in response to these agents is dependent on both Mdm2 levels and an intact ubiquitin ligase function. These findings reveal a novel, p53-independent activity of Mdm2 and have important implications for the choice of chemotherapeutic agents in the treatment of Mdm2-overexpressing tumors.

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Acknowledgements

We wish to thank the members of the Manfredi laboratory—Lois Resnick-Silverman, Luis Carvajal, Pierre-Jacques Hamard, Crystal Tonnessen and Nicolas Bartelery—as well as Matthew O’Connell, Miguel Gama-Sosa, Stuart Aaronson and Robert Maki for helpful discussions. We also wish to thank Jonathan Fletcher (Brigham and Women’s Hospital) for the LS141 liposarcoma cell line, Ze’ev Ronai (Sanford-Burnham Medical Research Institute) for the expression vector for Flag-tagged Mdm2WT and Shohreh Varmeh for the recombinant Adeno-Mdm2-GFP adenovirus. We wish to thank Carol Prives (Columbia University) for Trp53−/−MDM2+/+ and Trp53−/−Mdm2−/− MEFs. Joseph Tripodi and Vesna Najfeld are gratefully thanked for performing the FISH analysis. These studies were supported by National Cancer Institute grants T32CA078207 to JCS and R03CA216466 to JJM and developmental support from P30CA196521.

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  1. Department of Oncological Sciences and Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    J C Senturk, S Bohlman & J J Manfredi

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Senturk, J., Bohlman, S. & Manfredi, J. Mdm2 selectively suppresses DNA damage arising from inhibition of topoisomerase II independent of p53. Oncogene 36, 6085–6096 (2017). https://doi.org/10.1038/onc.2017.229

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