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

Oncotarget
Nian-Kang SunChuck C-K Chao

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 suppre...Continue Reading

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Citations

Feb 23, 2019·Cells·Taichi Mizushima, Hiroshi Miyamoto
Mar 14, 2021·Cell Chemical Biology·Dhanir TailorSanjay V Malhotra
Sep 30, 2021·Cellular and Molecular Life Sciences : CMLS·Samiksha KukalRitushree Kukreti

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Datasets Mentioned

BETA
GSE58840
MDAH-2774

Methods Mentioned

BETA
PCR
protein assay
immunoprecipitation
nuclear translocation

Software Mentioned

MetaCore
GenePix
Rosetta Resolver
GenePix Pro
MetaCore Analytical Suite

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