Oncotarget

Research Papers:

Pygopus2 inhibits the efficacy of paclitaxel-induced apoptosis and induces multidrug resistance in human glioma cells

Cefan Zhou, Hongxia Cheng, Wenying Qin, Yi Zhang, Hui Xiong, Jing Yang, Huang Huang, Yefu Wang, Xing-Zhen Chen and Jingfeng Tang _

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Oncotarget. 2017; 8:27915-27928. https://doi.org/10.18632/oncotarget.15843

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Abstract

Cefan Zhou1,2,*, Hongxia Cheng3,*, Wenying Qin1,*, Yi Zhang1, Hui Xiong4, Jing Yang5, Huang Huang1, Yefu Wang2, Xing-Zhen Chen1,6, Jingfeng Tang1

1Institute of Biomedical and Pharmaceutical Sciences, Key Laboratory of Fermentation Engineering (Ministry of Education), College of Bioengineering, Hubei University of Technology, Wuhan, 430068, China

2The State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China

3Department of Chemical and Pharmaceutical Engineering, Wuhan Huaxia University of Technology, Wuhan, 430223, China

4XiLi People's Hospital, Shenzhen, Guangdong, 518055, China

5Institute for Immunology, Tsinghua University, Beijing, 100084, China

6Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2R3, Canada

*These authors contributed equally to this work

Correspondence to:

Jingfeng Tang, email: Jingfeng_HUT@163.com

Keywords: Pygo2, paclitaxel, MDR1, P-glycoprotein, glioma

Received: November 16, 2016     Accepted: February 20, 2017     Published: March 02, 2017

ABSTRACT

Anti-microtubule drugs, such as paclitaxel (PTX), are extensively used for the treatment of numerous cancers. However, growing evidence has shown that PTX resistance, either intrinsic or acquired, frequently occurs in patients and results in the failure of treatment, contributing to the high cancer mortality rate. Therefore, it is necessary to identify the genes or pathways involved in anti-microtubule drug resistance for future successful treatment of cancers. Pygopus2 (Pygo2), which contains a Zn-coordinated plant homeodomain (PHD) finger domain, is critical for β-catenin-dependent transcriptional switches in normal and malignant tissues and is over-expressed in various cancers, including human brain glioma. In this study, we report that over-expression of Pygo2 inhibited the efficacy of PTX and contributed to cell multidrug resistance in two different ways. First, over-expression of Pygo2 inhibited the PTX-induced phosphorylation of B-cell lymphoma 2 (Bcl-2), suppressing the proteolytic cleavage of procaspase-8/9 and further inhibiting the activation of caspase-3, which also inhibits the activation of the JNK/SAPK pathway, ultimately inhibiting cell apoptosis. Second, over-expression of Pygo2 facilitated the expression of P-glycoprotein, which acts as a drug efflux pump, by promoting the transcription of Multi-drug resistance 1 (MDR1) at the MDR1 promoter loci, resulting in acceleration of the efflux of PTX.


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