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

Overview

Journal Cancer Biol Ther

Specialties Oncology
Pharmacology

Date 2018 Nov 22

PMID 30462562

Citations 12

Authors

Yangwei Fan

Mengya Li

Ke Ma

Yuan Hu

Jiayu Jing

Yu Shi

Enxiao Li

Danfeng Dong

Affiliations

Soon will be listed here.

Abstract

Triple-negative breast cancer (TNBC) has a poor prognosis mainly due to insensitivity or resistance to standard anthracycline- and taxane-based chemotherapy, urgently calling for new adjuvants to reverse drug resistance. Dual-target murine double minute 2 (MDM2) and murine double minute X (MDMX) inhibitor has been proved to play a critical part against cancer, particularly focusing on the tremendous potential to enhance the efficacy of doxorubicin (DOX), however little was reported in TNBC. In the present study, we investigated the synergistic antitumor effect of the MDM2/MDMX inhibitor with DOX using three TNBC cell lines, two in situ transplantation tumor models and 214 clinical samples. We observed that the MDM2/MDMX inhibitor combined with DOX could not only inhibit cell vitality and migration and invasion abilities, but also highly inhibit tumor growth in TNBC nude mice. Besides, co-treatment of MDM2/MDMX inhibitor and DOX suppressed epithelial to mesenchymal transition (EMT) through increasing the TAK1-binding protein 1 (TAB1), transforming growth factor β-activated kinase 1 (TAK1) and p38 mitogen-activated protein kinase (MAPK) expression. Small interfering RNA-mediated TAB1 knockdown induced the EMT, desensitized cells to DOX and enhanced the migration and invasion abilities. High MDM2/MDMX expression was positively associated with weak TAB1 expression in 214 TNBC tumor tissues confirmed by immumohistochemical staining and MDM2/MDMX/TAB1 expression was significantly related to TNBC patient survival. These findings indicate that dual-target MDM2/MDMX inhibitor could increase the sensitization of doxorubicin and inhibit migration and invasion abilities in TNBC cells through p38 MAPK pathway activation caused EMT suppression and hence could be useful in TNBC treatments in future.

Citing Articles

Pharmacological Inhibition of MDM2 Induces Apoptosis in p53-Mutated Triple-Negative Breast Cancer.

On J, Ghaderi S, Rittmann C, Hoffmann G, Gier F, Woloschin V Int J Mol Sci. 2025; 26(3).

PMID: 39940844 PMC: 11817430. DOI: 10.3390/ijms26031078.

MDM2: current research status and prospects of tumor treatment.

Yao Y, Zhang Q, Li Z, Zhang H Cancer Cell Int. 2024; 24(1):170.

PMID: 38741108 PMC: 11092046. DOI: 10.1186/s12935-024-03356-8.

MDMX in Cancer: A Partner of p53 and a p53-Independent Effector.

Lin W, Yan Y, Huang Q, Zheng D Biologics. 2024; 18:61-78.

PMID: 38318098 PMC: 10839028. DOI: 10.2147/BTT.S436629.

MDM2- an indispensable player in tumorigenesis.

Zafar A, Khan M, Naeem A Mol Biol Rep. 2023; 50(8):6871-6883.

PMID: 37314603 PMC: 10374471. DOI: 10.1007/s11033-023-08512-3.

Application of Microfluidic Systems for Breast Cancer Research.

Frankman Z, Jiang L, Schroeder J, Zohar Y Micromachines (Basel). 2022; 13(2).

PMID: 35208277 PMC: 8877872. DOI: 10.3390/mi13020152.

References

Hipp S, Berg D, Ergin B, Schuster T, Hapfelmeier A, Walch A . Interaction of Snail and p38 mitogen-activated protein kinase results in shorter overall survival of ovarian cancer patients. Virchows Arch. 2010; 457(6):705-13. DOI: 10.1007/s00428-010-0986-5. View

Johnson G, Lapadat R . Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002; 298(5600):1911-2. DOI: 10.1126/science.1072682. View

Creighton C, Li X, Landis M, Dixon J, Neumeister V, Sjolund A . Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009; 106(33):13820-5. PMC: 2720409. DOI: 10.1073/pnas.0905718106. View

Witte D, Otterbein H, Forster M, Giehl K, Zeiser R, Lehnert H . Negative regulation of TGF-β1-induced MKK6-p38 and MEK-ERK signalling and epithelial-mesenchymal transition by Rac1b. Sci Rep. 2017; 7(1):17313. PMC: 5725500. DOI: 10.1038/s41598-017-15170-6. View

Toledo F, Wahl G . Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006; 6(12):909-23. DOI: 10.1038/nrc2012. View

Qin J, 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. 2018; 8:917. PMC: 5735069. DOI: 10.3389/fphar.2017.00917. View

Chang Y, Graves B, Guerlavais V, Tovar C, Packman K, To K . Stapled α-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(36):E3445-54. PMC: 3767549. DOI: 10.1073/pnas.1303002110. View

Geng Q, Dong D, Chen N, Wu Y, Li E, Wang J . 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(6):1935-42. DOI: 10.3892/ijo.2013.2138. View

Ventura A, Kirsch D, McLaughlin M, Tuveson D, Grimm J, Lintault L . Restoration of p53 function leads to tumour regression in vivo. Nature. 2007; 445(7128):661-5. DOI: 10.1038/nature05541. View

10.

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

11.

Koul H, Pal M, Koul S . Role of p38 MAP Kinase Signal Transduction in Solid Tumors. Genes Cancer. 2013; 4(9-10):342-59. PMC: 3863344. DOI: 10.1177/1947601913507951. View

12.

Vassilev L, Vu B, Graves B, Carvajal D, Podlaski F, Filipovic Z . In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004; 303(5659):844-8. DOI: 10.1126/science.1092472. View

13.

Helfand B, Chang L, Goldman R . Intermediate filaments are dynamic and motile elements of cellular architecture. J Cell Sci. 2003; 117(Pt 2):133-41. DOI: 10.1242/jcs.00936. View

14.

Haupt S, Vijayakumaran R, Miranda P, Burgess A, Lim E, Haupt Y . The role of MDM2 and MDM4 in breast cancer development and prevention. J Mol Cell Biol. 2017; 9(1):53-61. PMC: 5439375. DOI: 10.1093/jmcb/mjx007. View

15.

Siegel R, Miller K, Jemal A . Cancer statistics, 2018. CA Cancer J Clin. 2018; 68(1):7-30. DOI: 10.3322/caac.21442. View

16.

Wheelock M, Johnson K . Cadherins as modulators of cellular phenotype. Annu Rev Cell Dev Biol. 2003; 19:207-35. DOI: 10.1146/annurev.cellbio.19.011102.111135. View

17.

Zheng X, Carstens J, Kim J, Scheible M, Kaye J, Sugimoto H . Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015; 527(7579):525-530. PMC: 4849281. DOI: 10.1038/nature16064. View

18.

Hazan R, Qiao R, Keren R, Badano I, Suyama K . Cadherin switch in tumor progression. Ann N Y Acad Sci. 2004; 1014:155-63. DOI: 10.1196/annals.1294.016. View

19.

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. J Biol Chem. 2000; 275(13):9492-500. DOI: 10.1074/jbc.275.13.9492. View

20.

Del Barco Barrantes I, Nebreda A . Roles of p38 MAPKs in invasion and metastasis. Biochem Soc Trans. 2012; 40(1):79-84. DOI: 10.1042/BST20110676. View