J Cancer 2020; 11(1):25-40. doi:10.7150/jca.32765

Research Paper

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

Yangwei Fan1*, Ke Ma2*, Jiayu Jing1, Chuying Wang1, Yuan Hu1, Yu Shi1, Enxiao Li1✉, Qianqian Geng3✉

1. Department of Medical Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an710061, China
2. Department of Medical Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou450052, China
3. Department of Nuclear Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an710061, China
*These authors contributed equally to this work

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Citation:
Fan Y, Ma K, Jing J, Wang C, Hu Y, Shi Y, Li E, Geng Q. 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. J Cancer 2020; 11(1):25-40. doi:10.7150/jca.32765. Available from http://www.jcancer.org/v11p0025.htm

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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.

Keywords: breast cancer, p53, MDM2, MDMX, MDR