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.

Androgen receptor transcriptional activity and chromatin modifications on the ABCB1/MDR gene are critical for taxol resistance in ovarian cancer cells

“…Moreover, ectopic expression of AR by AR plasmid in AR‐null HEK293 cells induced resistance to taxol by 1.8‐fold (Figure f). This observation is consistent with previous findings showing that AR expression and nuclear location affect taxol sensitivity in early stage of acquired txr (N. K. Sun et al, ). Similarly, ABCB1 mRNA level was also induced by taxol in HEK293 following transfection with AR complementary DNA (Figure g).…”

“…Taxol‐induced ABCB1 expression and chromatin modification was dramatically suppressed by the AKT inhibitor, but not by the other kinase inhibitors tested (Figure a). AR expression is dependent on AKT and JNK pathways in these cells as only AKT and JNK inhibitors (Wortmannin and SP600125, respectively) downregulated AR expression (N. K. Sun et al, ). These results suggest that the AKT pathway likely represents a target of sub‐lethal taxol treatment in upregulating ABCB1 expression.…”

Overexpression of caveolin-1 reduces Taxol resistance in human osteosarcoma cells by attenuating PI3K-Akt-JNK dependent autophagy

“…To investigate how CAV-1 reduces Taxol resistance and autophagy, the role of JNKs in this process was analyzed as JNKs have previously been reported to mediate Taxol resistance in ovarian carcinoma cells (19), and JNK1-mediated phosphorylation of B cell lymphoma-2 has an important role in the regulation of autophagy (20). To compare Taxol-resistant cells and their parent cells, the activation of the phosphorylation of JNK and upstream Akt was increased, suggesting an increase in JNK activity (Fig.…”

Inhibitor of Differentiation/DNA Binding 1 (ID1) Inhibits Etoposide-induced Apoptosis in a c-Jun/c-Fos-dependent Manner

“…Transcription factor AP-1 is mainly composed of Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra-1, and Fra-2) (20,21). Previous study showed that AP-1 is required for cell survival and involved in multidrug resistance (22,23). In this study, using ChIP and dual luciferase reporter assay, we show for the first time that c-Jun/c-Fos can directly bind to the ID1 promoter, thereby activating ID1 transcription and expression in vivo (Fig.…”

“…AP-1 is a mammalian transcription factor and collectively describes a group of structurally and functionally related members of the Jun protein family (c-Jun, JunB, and JunD) and Fos protein family (c-Fos, FosB, Fra-1, and Fra-2) (20,21). It has been reported that AP-1 is required for cell survival and involved in multidrug resistance (22,23). Recent research demonstrated that the aberrantly high levels of ID1 expression in cancer are often a consequence of transcriptional induction by many proteins that are activated in a constitutive manner in cancer cells and affect chemoresistance (24 -26).…”