Oncotarget

Research Papers:

Integrative transcriptomics-based identification of cryptic drivers of taxol-resistance genes in ovarian carcinoma cells: Analysis of the androgen receptor

Nian-Kang Sun, Shang-Lang Huang, Hsing-Pang Lu, Ting-Chang Chang and Chuck C.-K. Chao _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:27065-27082. https://doi.org/10.18632/oncotarget.4824

Metrics: PDF 1137 views  |   HTML 1214 views  |   ?  


Abstract

Nian-Kang Sun1,2,*, Shang-Lang Huang1,*, Hsing-Pang Lu1, Ting-Chang Chang3, Chuck C.-K. Chao1,4

1Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China

2Division of Biomedical Sciences, Chang Gung University of Science and Technology, Taoyuan, Taiwan, Republic of China

3Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan, Taiwan, Republic of China

4Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China

*These authors have contributed equally to this work

Correspondence to:

Chuck C.-K. Chao, e-mail: cckchao@mail.cgu.edu.tw

Keywords: androgen receptor, taxol, ovarian cancer, transcription factor, multiple drug resistance

Received: March 17, 2015     Accepted: July 31, 2015     Published: August 11, 2015

ABSTRACT

A systematic analysis of the genes involved in taxol resistance (txr) has never been performed. In the present study, we created txr ovarian carcinoma cell lines to identify the genes involved in chemoresistance. Transcriptome analysis revealed 1,194 overexpressed genes in txr cells. Among the upregulated genes, more than 12 cryptic transcription factors were identified using MetaCore analysis (including AR, C/EBPβ, ERα, HNF4α, c-Jun/AP-1, c-Myc, and SP-1). Notably, individual silencing of these transcription factors (except HNF4`)sensitized txr cells to taxol. The androgen receptor (AR) and its target genes were selected for further analysis. Silencing AR using RNA interference produced a 3-fold sensitization to taxol in txr cells, a response similar to that produced by silencing abcb1. AR silencing also downregulated the expression of prominent txr gene candidates (including abcb1, abcb6, abcg2, bmp5, fat3, fgfr2, h1f0, srcrb4d, and tmprss15). In contrast, AR activation using the agonist DHT upregulated expression of the target genes. Individually silencing seven out of nine (78%) AR-regulated txr genes sensitized txr cells to taxol. Inhibition of AKT and JNK cellular kinases using chemical inhibitors caused a dramatic suppression of AR expression. These results indicate that the AR represents a critical driver of gene expression involved in txr.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 4824