Dual-target MDM2/MDMX inhibitor increases the sensitization of doxorubicin and inhibits migration and invasion abilities of triple-negative breast cancer cells through activation of TAB1/TAK1/p38 MAPK pathway

References

• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30. doi:10.3322/caac.21442.
   PubMed Web of Science ®Google Scholar
• Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–132. doi:10.3322/caac.21338.
   PubMed Web of Science ®Google Scholar
• Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N. Triple-negative breast cancer–current status and future directions. Ann Oncol. 2009;20:1913–1927. doi:10.1093/annonc/mdp492.
   PubMed Web of Science ®Google Scholar
• Lehmann BD, Pietenpol JA. Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol. 2014;232:142–150. doi:10.1002/path.4280.
   PubMed Web of Science ®Google Scholar
• Giai M, Biglia N, Sismondi P. Chemoresistance in breast tumors. Eur J Gynaecol Oncol. 12;1991:359–373.
   PubMedGoogle Scholar
• Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops. Oncogene. 2005;24:2899–2908. doi:10.1038/sj.onc.1208615.
   PubMed Web of Science ®Google Scholar
• Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science (New York, NY). 1991;253:49–53. doi:10.1126/science.1905840.
   Web of Science ®Google Scholar
• Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007;445:661–665. doi:10.1038/nature05541.
   PubMed Web of Science ®Google Scholar
• Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;6:909–923. doi:10.1038/nrc2012.
   PubMed Web of Science ®Google Scholar
• Boehme KA, Blattner C. Regulation of p53–insights into a complex process. Crit Rev Biochem Mol Biol. 2009;44:367–392. doi:10.3109/10409230903401507.
   PubMed Web of Science ®Google Scholar
• Wade M, Li YC, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 13;2013:83–96.
   PubMed Web of Science ®Google Scholar
• Hu B, Gilkes DM, Farooqi B, Sebti SM, Chen J. MDMX overexpression prevents p53 activation by the MDM2 inhibitor nutlin. J Biol Chem. 2006;281:33030–33035. doi:10.1074/jbc.C600147200.
   PubMed Web of Science ®Google Scholar
• Haupt S, Vijayakumaran R, Miranda PJ, Burgess A, Lim E, Haupt Y. The role of MDM2 and MDM4 in breast cancer development and prevention. J Mol Cell Biol. 2017;9:53–61. doi:10.1093/jmcb/mjx007.
   PubMed Web of Science ®Google Scholar
• Marine JC, Francoz S, Maetens M, Wahl G, Toledo F, Lozano G. Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Cell Death Differ. 2006;13:927–934. doi:10.1038/sj.cdd.4401912.
   PubMed Web of Science ®Google Scholar
• Chang YS, Graves B, Guerlavais V, Tovar C, Packman K, To KH, Olson KA, Kesavan K, Gangurde P, Click Here to Enter Text. A, et al. Stapled alpha-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci U S A. 2013;110:E3445–54. doi:10.1073/pnas.1303002110.
   PubMed Web of Science ®Google Scholar
• Qin JJ, Li X, Wang W, Zi X, Zhang R. Targeting the NFAT1-MDM2-MDMX network inhibits the proliferation and invasion of prostate cancer cells, independent of p53 and androgen. Front Pharmacol. 2017;8:917. doi:10.3389/fphar.2017.00917.
   PubMed Web of Science ®Google Scholar
• Soares J, Espadinha M, Raimundo L, Ramos H, Gomes AS, Gomes S, Loureiro JB, Inga A, Reis F, Gomes C, et al. DIMP53-1: a novel small-molecule dual inhibitor of p53-MDM2/X interactions with multifunctional p53-dependent anticancer properties. Mol Oncol. 2017;11:612–627. doi:10.1002/1878-0261.12051.
   PubMed Web of Science ®Google Scholar
• Geng QQ, Dong DF, Chen NZ, Wu YY, Li EX, Wang J, Wang S-M. Induction of p53 expression and apoptosis by a recombinant dual-target MDM2/MDMX inhibitory protein in wild-type p53 breast cancer cells. Int J Oncol. 2013;43:1935–1942. doi:10.3892/ijo.2013.2138.
   PubMed Web of Science ®Google Scholar
• De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97–110. doi:10.1038/nrc3447.
   PubMed Web of Science ®Google Scholar
• Zavadil J, Haley J, Kalluri R, Muthuswamy SK, Thompson E. Epithelial-mesenchymal transition. Cancer Res. 2008;68:9574–9577. doi:10.1158/0008-5472.CAN-08-2316.
   PubMed Web of Science ®Google Scholar
• Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–1428. doi:10.1172/JCI39104.
   PubMed Web of Science ®Google Scholar
• Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29:4741–4751. doi:10.1038/onc.2010.215.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Toy KA, Kleer CG. Metaplastic breast carcinomas are enriched in markers of tumor-initiating cells and epithelial to mesenchymal transition. Modern Pathol. 2012;25:178–184. doi:10.1038/modpathol.2011.167.
   PubMed Web of Science ®Google Scholar
• Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, Rimm DL, Wong H, Rodriguez A, Herschkowitz JI, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009;106:13820–13825. doi:10.1073/pnas.0905718106.
   PubMed Web of Science ®Google Scholar
• Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Click Here to Enter Text. -C-C, LeBleu VS, Kalluri R. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527:525–530. doi:10.1038/nature16064.
   PubMed Web of Science ®Google Scholar
• Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong STC, Choi H, El Rayes T, Ryu S, Troeger J, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527:472–476. doi:10.1038/nature15748.
   PubMed Web of Science ®Google Scholar
• Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science (New York, NY). 2002;298:1911–1912. doi:10.1126/science.1072682.
   Google Scholar
• Koul HK, Pal M, Koul S. Role of p38 MAP Kinase Signal Transduction in Solid Tumors. Genes Cancer. 2013;4:342–359. doi:10.1177/1947601913507951.
   PubMedGoogle Scholar
• Zhu Y, Regunath K, Jacq X, Prives C. Cisplatin causes cell death via TAB1 regulation of p53/MDM2/MDMX circuitry. Genes Dev. 2013;27:1739–1751. doi:10.1101/gad.212258.112.
   PubMed Web of Science ®Google Scholar
• Witte D, Otterbein H, Forster M, Giehl K, Zeiser R, Lehnert H, Ungefroren H. Negative regulation of TGF-beta1-induced MKK6-p38 and MEK-ERK signalling and epithelial-mesenchymal transition by Rac1b. Sci Rep. 2017;7:17313. doi:10.1038/s41598-017-15170-6.
   PubMed Web of Science ®Google Scholar
• Zhao X, Wu X, Qian M, Song Y, Wu D, Zhang W. Knockdown of TGF-β1 expression in human umbilical cord mesenchymal stem cells reverts their exosome-mediated EMT promoting effect on lung cancer cells. Cancer Lett. 2018;428:34–44. doi:10.1016/j.canlet.2018.04.026.
   PubMed Web of Science ®Google Scholar
• del Barco Barrantes I, Nebreda AR. Roles of p38 MAPKs in invasion and metastasis. Biochem Soc Trans. 2012;40:79–84. doi:10.1042/BST20110676.
   PubMed Web of Science ®Google Scholar
• Shetzer Y, Solomon H, Koifman G, Molchadsky A, Horesh S, Rotter V. The paradigm of mutant p53-expressing cancer stem cells and drug resistance. Carcinogenesis. 2014;35:1196–1208. doi:10.1093/carcin/bgu073.
   PubMed Web of Science ®Google Scholar
• Wheelock MJ, Johnson KR. Cadherins as modulators of cellular phenotype. Annu Rev Cell Dev Biol. 2003;19:207–235. doi:10.1146/annurev.cellbio.19.011102.111135.
   PubMed Web of Science ®Google Scholar
• Christofori G. Changing neighbours, changing behaviour: cell adhesion molecule-mediated signalling during tumour progression. Embo J. 2003;22:2318–2323. doi:10.1093/emboj/cdg228.
   PubMed Web of Science ®Google Scholar
• Hazan RB, Qiao R, Keren R, Badano I, Suyama K. Cadherin switch in tumor progression. Ann N Y Acad Sci. 1014;2004:155–163.
   PubMed Web of Science ®Google Scholar
• Helfand BT, Chang L, Goldman RD. Intermediate filaments are dynamic and motile elements of cellular architecture. J Cell Sci. 2004;117:133–141. doi:10.1242/jcs.00936.
   PubMed Web of Science ®Google Scholar
• Reichert M, Muller T, Hunziker W. The PDZ domains of zonula occludens-1 induce an epithelial to mesenchymal transition of Madin-Darby canine kidney I cells. Evidence for a Role of beta-catenin/Tcf/Lef Signaling. The Journal of Biological Chemistry. 275;2000:9492–9500.
   PubMed Web of Science ®Google Scholar
• Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with snail and E47 repressors. J Cell Sci. 116;2003:499–511.
   PubMed Web of Science ®Google Scholar
• Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, Mikulits W, Brabletz T, Strand D, Obrist P, et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene. 2007;26:6979–6988. doi:10.1038/sj.onc.1210508.
   PubMed Web of Science ®Google Scholar
• Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science (New York, NY). 2004;303:844–848. doi:10.1126/science.1092472.
   Google Scholar
• Hong J, Zhou J, Fu J, He T, Qin J, Wang L, Liao L, Xu J. Phosphorylation of serine 68 of twist1 by MAPKs stabilizes twist1 protein and promotes breast cancer cell invasiveness. Cancer Res. 2011;71:3980–3990. doi:10.1158/0008-5472.CAN-10-2914.
   PubMed Web of Science ®Google Scholar
• Hipp S, Berg D, Ergin B, Schuster T, Hapfelmeier A, Walch A, Avril S, Schmalfeldt B, Höfler H, Becker K-F. Interaction of snail and p38 mitogen-activated protein kinase results in shorter overall survival of ovarian cancer patients. Virchows Archiv. 2010;457:705–713. doi:10.1007/s00428-010-0986-5.
   PubMed Web of Science ®Google Scholar
• Strippoli R, Benedicto I, Foronda M, Perez-Lozano ML, Sanchez-Perales S, Lopez-Cabrera M, Del Pozo MÁ. p38 maintains E-cadherin expression by modulating TAK1-NF-kappa B during epithelial-to-mesenchymal transition. J Cell Sci. 2010;123:4321–4331. doi:10.1242/jcs.071647.
   PubMed Web of Science ®Google Scholar
• Edge SB, Compton CC. The American joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–1474. doi:10.1245/s10434-010-0985-4.
   PubMed Web of Science ®Google Scholar
• Lebeau A, Kriegsmann M, Burandt E, Sinn HP. Invasive breast cancer: the current WHO classification. Der Pathologe. 2014;35:7–17. doi:10.1007/s00292-013-1841-7.
   PubMed Web of Science ®Google Scholar
• Sinicrope FA, Ruan SB, Cleary KR, Stephens LC, Lee JJ, Levin B. bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res. 55;1995:237–241.
   PubMed Web of Science ®Google Scholar