scholarly journals ING Tumour Suppressors and ING Splice Variants as Coregulators of the Androgen Receptor Signalling in Prostate Cancer

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2599
Author(s):  
Anna Melekhova ◽  
Aria Baniahmad
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Histone Deacetylases ◽  
Drug Targets ◽  
Splice Variants ◽  
Castration Resistance ◽  
Protein Coding ◽  
Tumour Suppressors ◽  
Regulation Of Cell Cycle

Prevention and overcoming castration resistance of prostate cancer (PC) remains one of the main unsolved problems in modern oncology. Hence, many studies are focused on the investigation of novel androgen receptor (AR) regulators that could serve as potential drug targets in disease therapy. Among such factors, inhibitor of growth (ING) proteins were identified. Some ING proteins act as AR transcriptional coregulators, indicating their relevance for PC research. The ING family consists of five protein-coding genes from ING1 to ING5 and pseudogene INGX. The ING genes were revealed through their sequence homology to the first identified ING1 from an in vivo screen. ING factors are a part of histone modification complexes. With the help of the conserved plant homeodomain (PHD) motif, ING factors bind to Histone 3 Lysine 4 (H3K4) methylation mark with a stronger affinity to the highest methylation grade H3K4me3 and recruit histone acetyltransferases (HAT) and histone deacetylases (HDAC) to chromatin. ING1 and ING2 are core subunits of mSIN3a-HDAC corepressor complexes, whereas ING3–5 interact with different HAT complexes that serve as coactivators. ING members belong to type II tumour suppressors and are frequently downregulated in many types of malignancies, including PC. As the family name indicates, ING proteins are able to inhibit cell growth and tumour development via regulation of cell cycle and cancer-relevant pathways such as apoptosis, cellular senescence, DNA repair, cell migration, invasion, and angiogenesis. Many ING splice variants that enhance the diversity of ING activity were discovered. However, it seems that the existence of multiple ING splice variants is underestimated, since alternative splice variants, such as the AR coregulators ING1 and ING3, counteract full-length ING and thus play an opposite functional role. These results open a novel prospective investigation direction in understanding ING factors biology in PC and other malignancies.

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.

scholarly journals Novel Membrane-associated Androgen Receptor Splice Variant Potentiates Proliferative and Survival Responses in Prostate Cancer Cells

2011 ◽  
Vol 286 (41) ◽  
pp. 36152-36160 ◽  
Author(s):  
Xi Yang ◽  
Zhiyong Guo ◽  
Feng Sun ◽  
Wei Li ◽  
Alan Alfano ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Plasma Membrane ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Splice Variant ◽  
Splice Variants ◽  
Response To Treatment ◽  
Castration Resistance ◽  
Prostate Cancer Cells ◽  
Castration Resistant

Progression from the androgen-sensitive to androgen-insensitive (or castration-resistant) stage is the major obstacle for sustained effectiveness of hormonal therapy for prostate cancer. The androgen receptor (AR) and its splice variants play important roles in regulating the transcription program essential for castration resistance. Here, we report the identification of a novel AR splice variant, designated as AR8, which is up-regulated in castration-resistant prostate cancer cells. AR8 is structurally different from other known AR splice variants because it lacks a DNA binding domain and therefore, unlikely functions as a transcription factor on its own. Immunofluorescence staining revealed that AR8 was primarily localized on the plasma membrane, possibly through palmitoylation of two cysteine residues within its unique C-terminal sequence. Mutation of these putative palmitoylation sites in AR8 led to loss of its plasma membrane localization. In addition, we demonstrated that overexpression of AR8 in prostate cancer cells promoted association of Src and AR with the EGF receptor in response to EGF treatment and enhanced tyrosine phosphorylation of AR. Conversely, specific knockdown of AR8 expression in prostate cancer cells compromised EGF-induced Src activation and AR phosphorylation. This effect was accompanied with attenuation of proliferation and increased apoptosis in prostate cancer cells cultured in androgen-depleted medium. We also showed that AR8 was required for optimal transcriptional activity of AR in response to treatment of both androgen and EGF. Taken together, our results demonstrate that the membrane-associated AR8 isoform may contribute to castration resistance by potentiating AR-mediated proliferative and survival responses to hormones and growth factors.

Blocking GRP/GRP-R Signaling Decreases Expression of Androgen Receptor Splice Variants and Inhibits Tumor Growth in Castration-resistant Prostate Cancer

2021 ◽  
Author(s):  
Thomas C Case ◽  
Alyssa Merkel ◽  
Marisol Ramirez-Solano ◽  
Qi Liu ◽  
Julie A Sterling ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Fluorescent Protein ◽  
Splice Variants ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Reporter Vector

Abstract Background: Clinical management of castration-resistant prostate cancer (CRPC) resulting from androgen deprivation therapy (ADT) remains challenging. Previously, we have reported that long-term ADT increases the neuroendocrine (NE) hormone – Gastrin Releasing Peptide (GRP) and its receptor (GRP-R) expression in prostate cancer (PC) cells. Further, we demonstrated that activation of GRP/GRP-R signaling increases androgen receptor (AR) splice variants (ARVs) expression through activating NF-κB signaling thereby contributing cancer progression to CRPC. Most importantly, as a cell surface protein, GRP-R is easily targeted by drugs to block GRP/GRP-R signaling. Here, we aim to investigate if blocking GRP/GRP-R signaling by targeting GRP-R using GRP-R antagonist is sufficient to control CRPC progression, including in therapy-induced (t) neuroendocrine prostate cancer (tNEPC). Methods: Bone-growing NEPC cells were generated by treating androgen dependent LNCaP PC cells with anti-androgen (MDV3100) for more than 3 months. RC-3095, a selective GRP-R antagonist, was used for blocking GRP/GRP-R signaling. The NGL vector [a NF-kB responsive reporter vector which has Luciferase and Green Fluorescent Protein (GFP) reporter genes] was used to measure NF-kB activity and the ARR2PB-Luc vector (an AR responsive reporter vector) was used to measure AR activity in the PC cells. For in vivo experiments, the effect of RC-3095 on CRPC was observed in subcutaneous CRPC and bone-growing tNEPC tumor models.Results: Our studies show that blocking GRP/GRP-R signal by targeting GRP-R using RC-3095 efficiently inhibits NF-κB activity and ARVs (AR-V7) expression in CRPC and tNEPC cells. In addition, blocking of GRP/GRP-R signaling by targeting GRP-R can sensitize CRPC cells to anti-androgen treatment. Further, preclinical animal studies indicate combination of GRP-R antagonist (targeting ARVs) with anti-androgen [targeting full-length AR (AR-FL)] is sufficient to inhibit CRPC and tNEPC tumor growth.Conclusion: Our findings strongly indicate that blocking of GRP/GRP-R signaling in combination with ADT is a potential new approach to control CRPC tumor growth, including ADT induced tNEPC.

Effect of generation 2.5 antisense inhibitor of androgen receptor on MDV3100-resistant prostate cancer cell growth in vitro and in vivo.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 94-94
Author(s):  
Yoshiaki Yamamoto ◽  
Eliana Beraldi ◽  
Yohann Loriot ◽  
Tianyuan Zhou ◽  
Youngsoo Kim ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Cell Lines ◽  
Splice Variants ◽  
Full Length ◽  
Castration Resistant Prostate Cancer ◽  
Exon 1 ◽  
Regulated Gene Expression

94 Background: MDV3100 is a potent androgen receptor (AR) antagonist with activity in castration resistant prostate cancer (CRPC); however, progression to MDV3100-resistant (MDV-R) CRPC frequently occurs with rising serum PSA levels, implicating AR full length or variants in disease progression. We studied the activity of Generation 2.5 antisense oligonucleotide (ASO) targeting the AR full length (ARfl) and splice variants in MDV-R CRPC models. Methods: and Results: ThreeASOs targeting exon 1, intron 1, or exon 8 were designed to suppress ARfl and known AR splice variants. We generated by selection MDV-R LNCaP-derived sub-lines that uniformly expressed high levels of both ARfl and AR-V7 compared to CRPC LNCaP cell lines. MDV-3100 induced time- and dose-dependent increases in ARfl and AR-V7 protein levels; ARfl levels were ~20-fold higher than AR-V7. All 3 AR-ASO decreased ARfl and PSA expression. Exon 1 ASO decreased expression of both ARfl and AR-V7 in MDV-R-LNCaP cells; in contrast, exon 8 ASO decreased ARfl without reducing AR-V7 levels. Exon 1 ASO also most potently suppressed ARfl and splice variants in M12 cells stably overexpressing AR splice variants AR-V7 and AR-V567es. Despite these differential effects on ARfl and splice variant knockdown, the AR ASO similarly inhibited cell growth and induced apoptosis and G1 cell cycle arrest in LNCaP-derived CRPC and MDV-R cell lines. In 22RV-1 cells (which express endogenous ARfl and AR-V7), exon 1 ASO more potently suppressed ARfl and AR-V7 levels, AR transcriptional activity and AR-regulated gene expression compared to exon 8 ASO, but inhibition of cell growth did not differ significantly. Exon 1 ASO was evaluated in vivo in MDV-R49F CRPC LNCaP xenografts; mean tumor volume and serum PSA levels decreased significantly by 40% and 50%, respectively, compared to controls. Conclusions: While MDV-3100 induces both ARfl and AR-V7 levels, the biologic consequences appear cell line dependent and mainly driven by ARfl. AR-ASO knockdown of ARfl and its splice variants suppresses MDV-R LNCaP tumor growth, providing pre-clinical proof of principle to support clinical evaluation in post-AR pathway inhibitor CRPC.

scholarly journals Expression of Androgen Receptor Splice Variants in Prostate Cancer Bone Metastases is Associated with Castration-Resistance and Short Survival

PLoS ONE ◽  
2011 ◽  
Vol 6 (4) ◽  
pp. e19059 ◽  
Author(s):  
Emma Hörnberg ◽  
Erik Bovinder Ylitalo ◽  
Sead Crnalic ◽  
Henrik Antti ◽  
Pär Stattin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Bone Metastases ◽  
Splice Variants ◽  
Castration Resistance ◽  
Short Survival ◽  
Androgen Receptor Splice Variants

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 AR Splicing Variants and Resistance to AR Targeting Agents

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2563
Author(s):  
Mayuko Kanayama ◽  
Changxue Lu ◽  
Jun Luo ◽  
Emmanuel S. Antonarakis
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Splice Variants ◽  
Treatment Options ◽  
Predictive Biomarker ◽  
Castration Resistant Prostate Cancer ◽  
Treatment Benefit ◽  
Novel Biomarkers ◽  
The Many ◽  
Preclinical And Clinical Studies

Over the past decade, advances in prostate cancer research have led to discovery and development of novel biomarkers and effective treatments. As treatment options diversify, it is critical to further develop and use optimal biomarkers for the purpose of maximizing treatment benefit and minimizing unwanted adverse effects. Because most treatments for prostate cancer target androgen receptor (AR) signaling, aberrations affecting this drug target are likely to emerge following the development of castration-resistant prostate cancer (CRPC), and it is conceivable that such aberrations may play a role in drug resistance. Among the many AR aberrations, we and others have been studying androgen receptor splice variants (AR-Vs), especially AR-V7, and have conducted preclinical and clinical studies to develop and validate the clinical utility of AR-V7 as a prognostic and potential predictive biomarker. In this review, we first describe mechanisms of AR-V generation, regulation and their functions from a molecular perspective. We then discuss AR-Vs from a clinical perspective, focusing on the significance of AR-Vs detected in different types of human specimens and AR-Vs as potential therapeutic targets.

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
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