Back to Search
Start Over
Recombinant Dual-target MDM2/MDMX Inhibitor Reverses Doxorubicin Resistance through Activation of the TAB1/TAK1/p38 MAPK Pathway in Wild-type p53 Multidrug-resistant Breast Cancer Cells
- Source :
- Journal of Cancer
- Publication Year :
- 2020
- Publisher :
- Ivyspring International Publisher, 2020.
-
Abstract
- Chemotherapy resistance represents a major obstacle for the treatment of patients with breast cancer (BC) and greatly restricts the therapeutic effect of the first-line chemotherapeutic agent doxorubicin (DOX). The present study aimed to investigate the feasibility of the recombinant dual-target murine double minute 2 (MDM2) and murine double minute X (MDMX) inhibitor in reversing the DOX resistance of BC. Both DOX-resistant human breast carcinoma cell lines exhibited a multidrug resistance (MDR) phenotype. The ability of the dual-target MDM2/MDMX inhibitor in reversing doxorubicin resistance was subsequently verified, (9.15 and 13.92 - fold reversal indexes) respectively. We observed that the MDM2/MDMX inhibitor in combination with DOX could suppress proliferation, promote cell cycle arrest and induce apoptosis. In addition, it was capable of reducing rhodamine123 efflux in DOX-resistance BC cell lines and further played a key role in BC nude mice model. The groups that were treated with the combination of the drugs had decreased P-glycoprotein/multidrug resistance-associated protein/cdc 2/Bcl-2 expression and increased CyclinB1/Bax expression. These effects were caused due to activation of the transforming growth factor β-activated kinase 1 (TAK1)-binding protein 1 (TAB1)/TAK1/p38 mitogen-activated protein kinase (MAPK) signaling pathway, as shown by small interfering RNA (siRNA) silencing and immumohistochemical staining of BC tissue sections. Furthermore, high MDM2/MDMX expression was positively associated with weak TAB1 expression in BC patients. Therefore, the recombinant dual-target MDM2/MDMX inhibitor could reverse doxorubicin resistance via the activation of the TAB1/TAK1/p38 MAPK pathway in wild-type p53 multidrug-resistant BC.
- Subjects :
- p53
0301 basic medicine
MAPK/ERK pathway
Small interfering RNA
MDMX
03 medical and health sciences
breast cancer
0302 clinical medicine
MDM2
MDR
medicine
Doxorubicin
Protein kinase A
biology
Kinase
Chemistry
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Cancer research
biology.protein
Mdm2
Signal transduction
Research Paper
medicine.drug
Subjects
Details
- ISSN :
- 18379664
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Journal of Cancer
- Accession number :
- edsair.doi.dedup.....ac28ad8a29bf8e9cb7f718ae31570484