MicroRNA Regulation of Androgen Receptor in Castration-Resistant Prostate Cancer: Premises, Promises, and Potentials

2020 ◽  
Vol 13 ◽  
Author(s):  
Safieh Ebrahimi ◽  
Seyed Isaac Hashemy ◽  
Amirhossein Sahebkar ◽  
Seyed Hamid AghaeeBakhtiari
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Therapeutic Potential ◽  
Splice Variants ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Contributing Factors ◽  
Development Of Resistance ◽  
Castration Resistant

: Prostate cancer (PCa) is the second most prevalent cancer and the fifth leading cause of cancer-related deaths among men. Androgen deprivation therapy (ADT) is the most frequently used therapeutic strategy in PCa; however, the development of resistance to ADT, known as castration-resistant prostate cancer (CRPC), continues to be a major obstacle against successful treatment of PCa. The abnormal activation of the androgen receptor (AR) signaling pathway has been found as one of the main contributing factors to the development of resistance in CRPC. Therefore, AR regulatory strategies are urgently required to combat resistance. Recently, microRNAs (miRNAs) have been found as major AR regulatory factors affecting ADT resistance. MiRNAs can target AR itself, AR-related genes, AR splice variants, ARrelated signaling pathways as well as cancer stem cells (CSCs), and play critical roles in regulating ADT resistance. Due to their capability to affect various genes and signaling pathways, miRNAs are now being studied for their potential role as a new therapeutic target in CRPC. It has been recommended that combination therapies including miRNAs and existing drugs can synergistically decrease castration resistance. miRNAs have also prognostic values for ADT, and their expression profiling in CRPC patients before therapeutic scheduling may enable the physician to diagnose patients who are ADT-resistant. Overall, extant evidence obviously supports the predictive and therapeutic potential of miRNAs in CRPC patients. This review summarizes the available information about the microRNA-mediated AR controlling mechanisms involved in ADT resistance.

Y-box binding protein-1 promotes castration-resistant prostate cancer growth via androgen receptor expression

2011 ◽  
Vol 18 (4) ◽  
pp. 505-517 ◽  
Author(s):  
Masaki Shiota ◽  
Ario Takeuchi ◽  
YooHyun Song ◽  
Akira Yokomizo ◽  
Eiji Kashiwagi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Therapeutic Potential ◽  
Binding Protein ◽  
Receptor Expression ◽  
Transcriptional Level ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Castration Resistant

The androgen receptor (AR) is well known to play a central role in the pathogenesis of prostate cancer (PCa). In several studies, AR was overexpressed in castration-resistant PCa (CRPC). However, the mechanism of AR overexpression in CRPC is not fully elucidated. Y-box binding protein-1 (YB-1) is a pleiotropic transcription factor that is upregulated in CPRC. We aimed to elucidate the role of YB-1 in castration resistance of PCa and identify therapeutic potential of targeting YB-1. Using immunohistochemistry, we found that nuclear YB-1 expression significantly correlated with the Gleason score and AR expression in PCa tissues. In PCa cells, YB-1 regulated AR expression at the transcriptional level. Furthermore, YB-1 expression and nuclear localization were upregulated in CRPC cells. Overexpression of AR, as well as YB-1, conferred castration-resistant growth in LNCaP and 22Rv1 cells. Conversely, knocking down YB-1 resulted in suppressed cell growth and induced apoptosis, which was more efficient than knocking down AR in LNCaP cells. In other types of PCa cells, such as CRPC cells, knocking down YB-1 resulted in a significant reduction of cell growth. In conclusion, these findings suggested that YB-1 induces castration resistance in androgen-dependent PCa cells via AR expression. Thus, YB-1 may be a promising therapeutic target for PCa, as well as CRPC.

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

scholarly journals Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3488
Author(s):  
Fuqiang Ban ◽  
Eric Leblanc ◽  
Ayse Derya Cavga ◽  
Chia-Chi Flora Huang ◽  
Mark R. Flory ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Splice Variants ◽  
Full Length ◽  
Cancer Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Terminal Domain ◽  
Castration Resistant ◽  
Coregulatory Proteins ◽  
Androgen Binding

Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or through the expression of constitutively active splice variants lacking the androgen binding domain entirely (e.g., ARV7). In this study, we are reporting the discovery of a novel AR-NTD covalent inhibitor 1-chloro-3-[(5-([(2S)-3-chloro-2-hydroxypropyl]amino)naphthalen-1-yl)amino]propan-2-ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and known coactivators and coregulatory proteins, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule that can be further optimized into effective AR-NTD inhibitor for the treatment of CRPC.

scholarly journals Data of relative mRNA and protein abundances of androgen receptor splice variants in castration-resistant prostate cancer

Data in Brief ◽  
2021 ◽  
Vol 34 ◽  
pp. 106774
Author(s):  
Tianfang Ma ◽  
Nathan Ungerleider ◽  
Derek Y. Zhang ◽  
Eva Corey ◽  
Erik K. Flemington ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Splice Variants ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Androgen Receptor Splice Variants

scholarly journals Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Yuan Liu ◽  
Cuifu Yu ◽  
Zhenlong Shao ◽  
Xiaohong Xia ◽  
Tumei Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Selective Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Selective Degradation ◽  
Castration Resistant ◽  
Novel Drugs ◽  
The Stability ◽  
Androgen Receptor Splice Variant

AbstractAndrogen receptor splice variant 7 (AR-V7), a form of ligand-independent and constitutively activating variant of androgen receptor (AR), is considered as the key driver to initiate castration-resistant prostate cancer (CRPC). Because AR-V7 lacks ligand-binding domain, the AR-targeted therapies that aim to inactivate AR signaling through disrupting the interaction between AR and androgen are limited in CRPC. Thus, the emergence of AR-V7 has become the greatest challenge for treating CRPC. Targeting protein degradation is a recently proposed novel avenue for cancer treatment. Our previous studies have been shown that the oncoprotein AR-V7 is a substrate of the proteasome. Identifying novel drugs that can trigger the degradation of AR-V7 is therefore critical to cure CRPC. Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells. Mechanically, we unravel that nobiletin selectively induces proteasomal degradation of AR-V7 (but not AR). This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.

scholarly journals Isoform specific activities of androgen receptor and its splice variants in prostate cancer cells

Endocrinology ◽  
2020 ◽  
Author(s):  
Harika Nagandla ◽  
Matthew J Robertson ◽  
Vasanta Putluri ◽  
Nagireddy Putluri ◽  
Cristian Coarfa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Gene ◽  
Target Genes ◽  
Splice Variants ◽  
Clinical Samples ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Specific Activities ◽  
Lncap Prostate Cancer Cell

Abstract Androgen receptor (AR) signaling continues to drive castration resistant prostate cancer (CRPC) in spite of androgen deprivation therapy (ADT). Constitutively active shorter variants of AR, lacking the ligand binding domain, are frequently expressed in CRPC and have emerged as a potential mechanism for prostate cancer to escape ADT. ARv7 and AR v567es are two of the most commonly detected variants of AR in clinical samples of advanced, metastatic prostate cancer. It is not clear if variants of AR merely act as weaker substitutes for AR or can mediate unique isoform specific activities different from AR. In this study, we employed LNCaP prostate cancer cell lines with inducible expression of ARv7 or AR v567es to delineate similarities and differences in transcriptomics, metabolomics and lipidomics resulting from the activation of AR, ARv7 or AR v567es. While the majority of target genes were similarly regulated by the action of all three isoforms, we found a clear difference in transcriptomic activities of AR versus the variants, and a few differences between ARv7 and AR v567es. Some of the target gene regulation by AR isoforms was similar in the VCaP background as well. Differences in downstream activities of AR isoforms were also evident from comparison of the metabolome and lipidome in an LNCaP model. Overall our study implies that shorter variants of AR are capable of mediating unique downstream activities different from AR and some of these are isoform specific.

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