title: Integrative transcriptomics-based identification of cryptic drivers of taxol-resistance genes in ovarian carcinoma cells: Analysis of the androgen receptor.
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.
authors: Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.|Division of Biomedical Sciences, Chang Gung University of Science and Technology, Taoyuan, Taiwan, Republic of China.
authors: Nian-Kang
authors: NK
authors: Sun
authors: Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.
authors: Shang-Lang
authors: SL
authors: Huang
authors: Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.
authors: Hsing-Pang
authors: HP
authors: Lu
authors: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan, Taiwan, Republic of China.
authors: Ting-Chang
authors: TC
authors: Chang
authors: Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.|Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.
authors: Chuck C-K
authors: CC
authors: Chao
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000235:genetics; D010051:Ovarian Neoplasms / Q000378:metabolism*; D017239:Paclitaxel / Q000737:chemistry*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000378:metabolism; D034622:RNA Interference; D011944:Receptors, Androgen / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: C410798:AR protein, human; D000972:Antineoplastic Agents, Phytogenic; D009841:Oligonucleotides; D011944:Receptors, Androgen; D014157:Transcription Factors; D017239:Paclitaxel
keywords: androgen receptor; multiple drug resistance; ovarian cancer; taxol; transcription factor