Replication study: androgen receptor splice variants determine taxane sensitivity in prostate cancer

Shan, Xiaochuan; Danet-Desnoyers, Gwenn; Aird, Fraser; Kandela, Irawati; Tsui, Rachel; Perfito, Nicole; Iorns, Elizabeth

doi:10.7717/peerj.4661

Cited by 3 publications

(3 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study suggested that AR splice variants may also affect sensitivity to taxanes and that tumors predominantly expressing the ARv7 variant, associated with ADT resistance, would also likely be resistant to DTX [ 47 ]. However, an independent group was unable to replicate these results under similar experimental conditions [ 48 ]. Furthermore, another group found that detection of ARv7 in circulating tumor cells of mCRPC patients was not associated with taxane-resistance and that certain patients with ARv7-positive status at baseline converted to ARv7-negative status during the course of taxane therapy, adding uncertainty to the clinical significance of this variant in patients receiving taxanes [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

RNA sequencing reveals upregulation of a transcriptomic program associated with stemness in metastatic prostate cancer cells selected for taxane resistance

et al. 2018

View full text Add to dashboard Cite

Patients with metastatic castration-resistant prostate cancer (mCRPC) develop resistance to conventional therapies including docetaxel (DTX). Identifying molecular pathways underlying DTX resistance is critical for developing novel combinatorial therapies to prevent or reverse this resistance. To identify transcriptomic signatures associated with acquisition of chemoresistance we profiled gene expression in DTX-sensitive and -resistant mCRPC cells using RNA sequencing (RNA-seq). PC3 and DU145 cells were selected for DTX resistance and this phenotype was validated by immunoblotting using DTX resistance markers (e.g. clusterin, ABCB1/P-gp, and LEDGF/p75). Overlapping genes differentially regulated in the DTX-sensitive and -resistant cells were ranked by Gene Set Enrichment Analysis (GSEA) and validated to correlate transcript with protein expression. GSEA revealed that genes associated with cancer stem cells (CSC) (e.g., NES, TSPAN8, DPPP, DNAJC12, and MYC) were highly ranked and comprised 70% of the top 25 genes differentially upregulated in the DTX-resistant cells. Established markers of epithelial-to-mesenchymal transition (EMT) and CSCs were used to evaluate the stemness of adherent DTX-resistant cells (2D cultures) and tumorspheres (3D cultures). Increased formation and frequency of cells expressing CSC markers were detected in DTX-resistant cells. DU145-DR cells showed a 2-fold increase in tumorsphere formation and increased DTX resistance compared to DU145-DR 2D cultures. These results demonstrate the induction of a transcriptomic program associated with stemness in mCRPC cells selected for DTX resistance, and strengthen the emerging body of evidence implicating CSCs in this process. In addition, they provide additional candidate genes and molecular pathways for potential therapeutic targeting to overcome DTX resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

RNA sequencing reveals upregulation of a transcriptomic program associated with stemness in metastatic prostate cancer cells selected for taxane resistance

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In the United States, ~1 out of 5 men will be diagnosed with PCa (4), while in China, the incidence of PCa is 7.1/100,000 individuals (7). Although PCa has a 5-year survival rate of 98.6% (4,8), an in-depth understanding of its pathogenesis and new therapeutic strategies are still urgently required.…”

Section: Introductionmentioning

confidence: 99%

Circular RNA UBAP2 promotes the proliferation of prostate cancer cells via the miR‑1244/MAP3K2 axis

Azhati

Wang

et al. 2021

Oncol Lett

View full text Add to dashboard Cite

Prostate cancer (PCa) is a common male malignant disease with a high incidence, which can seriously affect the quality of life of patients. The survival rate of patients with PCa has improved to 98.6%; however, new insights for the molecular mechanism are still urgently required. Circular RNA (circ)UBAP2 is a tumor-associated circRNA that has been demonstrated to promote the progression of various types of cancer. CircUBAP2 has been demonstrated to be significantly upregulated in PCa, but its role in the progression of PCa remains unclear. The present study aimed to provide an improved understanding of the regulatory mechanism of circUBAP2 in PCa. circUBAP2 expression was identified to be upregulated in four PCa cell lines and clinical tissues by using reverse transcription-quantitative PCR analysis. Binding sites analysis and luciferase reporter gene assay indicated that the microRNA(miR)-1244/MAP3K2 axis was the target of circUBAP2. Gain-of-function assays revealed that circUBAP2 promoted the proliferation of PCa cells by sponging miR-1244 and promoting the MAP3K2 axis. The present findings may be essential for providing new strategies in the diagnosis and targeted therapy of PCa.

show abstract

“…They showed that AR-V7 expressing tumor xenografts were resistant to docetaxel therapy while ARV567es expressing xenografts were highly sensitive to docetaxel. Of note, these results were unable to be independently replicated by a second group in the same xenograft models [37] . Zhang et al.…”

Section: The Ar Variantsmentioning

confidence: 85%

Current strategies for targeting the activity of androgen receptor variants

Armstrong

Gao

2019

Asian Journal of Urology

View full text Add to dashboard Cite

Current therapies for advanced prostate cancer, such as enzalutamide and abiraterone, focus on inhibiting androgen receptor (AR) activity and reducing downstream signaling pathways to inhibit tumor growth. Unfortunately, cancer cells are very adaptable and, over time, these cells develop mechanisms by which they can circumvent therapeutics. One of the many mechanisms that have been discovered is the generation of AR variants. These variants are generated through alternative splicing of the full length AR and often lack the ligand binding domain. This leads to forms of the AR that are constitutively active that continue to promote prostate cancer cell growth even in the absence of ligand. The high prevalence of AR variants and their role in disease progression have prompted a number of studies investigating ways to inhibited AR variant expression and activity. Among these are the anti-helminthic drug, niclosamide, which selectively promotes degradation of AR variants over full length AR and re-sensitizes anti-androgen resistant prostate cancer cells to treatment with enzalutamide and abiraterone. Other AR variant targeting mechanisms include interfering with AR variant co-activators and the development of drugs that bind to the DNA or N-terminal AR domains, which are retained in most AR variants. The clinical efficacy of treating prostate cancer by targeting AR variants is under investigation in several clinical trials. In this review, we provide an overview of the most relevant AR variants and discuss current AR variant targeting strategies.

show abstract

Replication study: androgen receptor splice variants determine taxane sensitivity in prostate cancer

Cited by 3 publications

References 9 publications

RNA sequencing reveals upregulation of a transcriptomic program associated with stemness in metastatic prostate cancer cells selected for taxane resistance

RNA sequencing reveals upregulation of a transcriptomic program associated with stemness in metastatic prostate cancer cells selected for taxane resistance

Circular RNA UBAP2 promotes the proliferation of prostate cancer cells via the miR‑1244/MAP3K2 axis

Current strategies for targeting the activity of androgen receptor variants

Contact Info

Product

Resources

About