Pharmacologically increasing Mdm2 inhibits DNA repair and cooperates with genotoxic agents to kill p53-inactivated ovarian cancer cells

Molecular Cancer Research

Volumn 13, Issue 8, 2015, Pages 1197-1205

  Carrillo, Alexia M ^a   Hicks, Mellissa ^a   Khabele, Dineo ^b   Eischen, Christine M ^a  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VANDERBILT UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA ACTIN; CASPASE 3; CISPLATIN; CYCLOHEXIMIDE; ETOPOSIDE; HISTONE H2AX; MRE11 PROTEIN; NIBRIN; NUTLIN 3; PROTEIN MDM2; PROTEIN P53; RAD50 PROTEIN; ANTINEOPLASTIC AGENT; IMIDAZOLE DERIVATIVE; MDM2 PROTEIN, HUMAN; MDM2 PROTEIN, MOUSE; MUTAGENIC AGENT; PIPERAZINE DERIVATIVE; TP53 PROTEIN, HUMAN;

ANIMAL CELL; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CANCER INHIBITION; CELL EXPANSION; CELL KILLING; CELL PROLIFERATION; CELL VIABILITY; CONTROLLED STUDY; DNA DAMAGE; DNA REPAIR; DNA STRAND BREAKAGE; DOUBLE STRANDED DNA BREAK; EMBRYO; FEMALE; HUMAN; HUMAN CELL; NONHUMAN; OVARIAN CANCER CELL LINE; OVARY CANCER; PRIORITY JOURNAL; PROTEIN STABILITY; ANIMAL; CHEMISTRY; COMET ASSAY; DRUG EFFECTS; FIBROBLAST; GENETICS; HEK293 CELL LINE; METABOLISM; MOUSE; OVARY TUMOR; TRANSGENIC MOUSE; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; APOPTOSIS; CELL LINE, TUMOR; CELL PROLIFERATION; CISPLATIN; COMET ASSAY; DNA BREAKS, DOUBLE-STRANDED; DNA DAMAGE; DNA REPAIR; ETOPOSIDE; FEMALE; FIBROBLASTS; HEK293 CELLS; HUMANS; IMIDAZOLES; MICE; MICE, TRANSGENIC; MUTAGENS; OVARIAN NEOPLASMS; PIPERAZINES; PROTO-ONCOGENE PROTEINS C-MDM2; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84942411527     PISSN: 15417786     EISSN: 15573125     Source Type: Journal    
DOI: 10.1158/1541-7786.MCR-15-0089     Document Type: Article

References (28)

1. Eischen CM, Lozano G. The Mdm network and its regulation of p53 activities: a rheostat of cancer risk. Hum Mutat 2014;35:728-37.
2. TCGA. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-15.
3. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.
4. Kyrgiou M, Salanti G, Pavlidis N, Paraskevaidis E, Ioannidis JP. Survival benefits with diverse chemotherapy regimens for ovarian cancer: meta-analysis of multiple treatments. J Natl Cancer Inst 2006;98:1655-63.
5. Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1998;16:405-10.
6. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004;303:844-8.
7. Khoo KH, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov 2014;13:217-36.
8. Li X, Gilkes D, Li B, Cheng Q, Pernazza D, Lawrence H, et al. Abnormal MDMX degradation in tumor cells due to ARF deficiency. Oncogene 2012;31:3721-32.
9. Melo AN, Eischen CM. Protecting the genome from mdm2 and mdmx. Genes Cancer 2012;3:283-90.
10. Alt JR, Bouska A, Fernandez MR, Cerny RL, Xiao H, Eischen CM. Mdm2 binds to Nbs1 at sites of DNA damage and regulates double-strand break repair. J Biol Chem 2005;280:18771-81.
11. Bouska A, Lushnikova T, Plaza S, Eischen CM. Mdm2 promotes genetic instability and transformation independent of p53. Mol Cell Biol 2008;28:4862-74.
12. Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, et al. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 1998;12:2424-33.
13. Khabele D, Son DS, Parl AK, Goldberg GL, Augenlicht LH, Mariadason JM, et al. Drug-induced inactivation or gene silencing of class I histone deacetylases suppresses ovarian cancer cell growth: implications for therapy. Cancer Biol Ther 2007;6:795-801.
14. Carrillo AM, Bouska A, Arrate MP, Eischen CM. Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene 2015;34:846-56.
15. Konstantinopoulos PA, Wilson AJ, Saskowski J, Wass E, Khabele D. Suberoylanilide hydroxamic acid (SAHA) enhances olaparib activity by targeting homologous recombination DNA repair in ovarian cancer. Gynecol Oncol 2014;133:599-606.
16. Williams BR, Mirzoeva OK, Morgan WF, Lin J, Dunnick W, Petrini JH. A murine model of Nijmegen breakage syndrome. Curr Biol 2002;12:648-53.
17. Bekker-Jensen S, Mailand N. Assembly and function of DNAdouble-strand break repair foci in mammalian cells. DNA Repair 2010;9:1219-28.
18. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER III, Hurov KE, Luo J, et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 2007;316:1160-6.
19. O'Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, et al. Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res 1997;57:4285-300.
20. Muggia F. Platinumcompounds 30 years after the introduction of cisplatin: implications for the treatment of ovarian cancer. Gynecol Oncol 2009;112:275-81.
21. Wang P, Lushnikova T, Odvody J, Greiner TC, Jones SN, Eischen CM. Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells. Oncogene 2008;27:1590-8.
22. Li Q, Zhang Y, El-Naggar AK, Xiong S, Yang P, Jackson JG, et al. Therapeutic efficacy of p53 restoration in Mdm2-overexpressing tumors. Mol Cancer Res 2014;12:901-11.
23. Conradt L, Henrich A, Wirth M, Reichert M, Lesina M, Algul H, et al. Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death. Int J Cancer 2013;132:2248-57.
24. Ambrosini G, Sambol EB, Carvajal D, Vassilev LT, Singer S, Schwartz GK. Mouse double minute antagonist Nutlin-3a enhances chemotherapyinduced apoptosis in cancer cells with mutant p53 by activating E2F1. Oncogene 2007;26:3473-81.
25. Lau LM, Nugent JK, Zhao X, Irwin MS. HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function. Oncogene 2008;27:997-1003.
26. Peirce SK, Findley HW. The MDM2 antagonist nutlin-3 sensitizes p53-null neuroblastoma cells to doxorubicin via E2F1 and TAp73. Int J Oncol 2009;34:1395-402.
27. Ray RM, Bhattacharya S, Johnson LR. Mdm2 inhibition induces apoptosis in p53 deficient human colon cancer cells by activating p73- and E2F1-mediated expression of PUMA and Siva-1. Apoptosis 2011;16:35-44.
28. Urist M, Tanaka T, Poyurovsky MV, Prives C. p73 induction after DNA damage is regulated by checkpoint kinases Chk1 and Chk2. Genes Dev 2004;18:3041-54.