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

• Published in: Oncogene 2017-11, Vol.36 (44), p.6085-6096
• Main Authors: Senturk, J C, Bohlman, S, Manfredi, J J
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/2; 13/31; 13/51; 13/89; 42; 42/109; 631/337/1427/2566; 631/67/1059; Animals; Antineoplastic Agents - administration & dosage; Apoptosis; Apoptosis - drug effects; Cancer; Cell Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Deoxyribonucleic acid; Development and progression; DNA; DNA Breaks, Double-Stranded - drug effects; DNA damage; DNA Damage - drug effects; DNA topoisomerase (ATP-hydrolysing); DNA Topoisomerases, Type II - genetics; Dosage and administration; Doxorubicin; Doxorubicin - administration & dosage; Drug interactions; Drug therapy; Etoposide; Etoposide - administration & dosage; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; MDM2 protein; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Oncogenes; Oncology; Oncology, Experimental; original-article; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - pathology; p53 Protein; Proto-Oncogene Proteins c-mdm2 - genetics; Topoisomerase II; Topoisomerase II Inhibitors - administration & dosage; Treatment resistance; Tumor cells; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumors; Ubiquitin; Ubiquitin-protein ligase
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.229

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.