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Androgen receptor splice variants

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https://www.readbyqxmd.com/read/28246761/-antihormonal-therapy-in-prostate-cancer-side-effects
#1
C H Ohlmann, P Thelen
Androgen deprivation is still standard therapy for prostate cancer, either as primary androgen deprivation therapy or with the use of secondary hormonal drugs including abiraterone and enzalutamide. However, especially the clinically occult side effects like metabolic changes or cardiovascular complications and effects on the psyche of the patient are often not recognized in daily practice. Active monitoring of such side effects is essential for prevention and early intervention. In addition, the efficacy of androgen deprivation therapies is limited by primary and secondary resistance...
February 28, 2017: Der Urologe. Ausg. A
https://www.readbyqxmd.com/read/28239558/role-of-androgen-receptor-splice-variants-in-prostate-cancer-metastasis
#2
Jin Xu, Yun Qiu
Prostate cancer (PCa) is one of the most lethal cancers in western countries. Androgen receptor (AR) signaling pathway plays a key role in PCa progression. Despite the initial effectiveness of androgen deprivation therapy (ADT) for treatment of patients with advanced PCa, most of them will develop resistance to ADT and progress to metastatic castration resistant prostate cancer (mCRPC). Constitutively transcriptional activated AR splice variants (AR-Vs) have emerged as critical players in the development and progression of mCRPC...
October 2016: Asian J Urol
https://www.readbyqxmd.com/read/28235766/sigma1-targeting-to-suppress-aberrant-androgen-receptor-signaling-in-prostate-cancer
#3
Jeffrey D Thomas, Charles G Longen, Halley M Oyer, Nan Chen, Christina M Maher, Joseph M Salvino, Blase Kania, Kelsey N Anderson, William F Ostrander, Karen E Knudsen, Felix J Kim
Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways...
February 24, 2017: Cancer Research
https://www.readbyqxmd.com/read/28224650/androgen-receptor-splice-variants-are-not-substrates-of-nonsense-mediated-decay
#4
Atinuke S Ajiboye, David Esopi, Srinivasan Yegnasubramanian, Samuel R Denmeade
BACKGROUND: Androgen receptor (AR) splice variants have been clinically associated with progressive cancer, castration-resistance, and resistance to AR antagonists and androgen synthesis inhibitors. AR variants can be generated by genomic alterations and alternative splicing, and their expression is androgen-regulated. There has been a suggestion that AR variants bearing premature termination codons and coding for truncated proteins should be regulated by the nonsense-mediated decay (NMD) mRNA surveillance pathway, suggesting that either the NMD pathway is dysfunctional in variant-expressing cell lines or that variants are somehow able to evade degradation by NMD...
February 22, 2017: Prostate
https://www.readbyqxmd.com/read/28209757/cdk4-6-therapeutic-intervention-and-viable-alternative-to-taxanes-in-crpc
#5
James P Stice, Suzanne E Wardell, John D Norris, Alexander P Yllanes, Holly M Alley, Victoria O Haney, Hannah S White, Rachid Safi, Peter S Winter, Kimberly J Cocce, Rigel J Kishton, Scott A Lawrence, Jay C Strum, Donald P McDonnell
Resistance to second generation AR antagonists and CYP17 inhibitors in patients with castrationresistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to androgen receptor (AR) overexpression, production of constitutively active AR splice variants, or the selection for AR mutants with altered ligand binding specificity. It has been established that androgens induce cell cycle progression, in part, through upregulation of cyclin D1 (CCND1) expression and subsequent activation of cyclin-dependent kinases 4 and 6 (CDK4/6)...
February 16, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28205582/aurora-a-regulates-expression-of-ar-v7-in-models-of-castrate-resistant-prostate-cancer
#6
Dominic Jones, Martin Noble, Steve R Wedge, Craig N Robson, Luke Gaughan
Androgen receptor variants (AR-Vs) provide a mechanism of therapy evasion in castrate-resistant prostate cancer (CRPC), yet mechanisms of regulation remain largely unknown. Here we investigate the role of Aurora A kinase on AR-Vs in models of CRPC and show depletion of Aurora A reduces AR-V target gene expression. Importantly, knockdown of Aurora A reconfigures splicing of AR pre-mRNA to discriminately down-regulate synthesis of AR-V transcripts, including AR-V7, without effecting full-length AR mRNA; and as a consequence, AR-V-driven proliferation and survival of CRPC cells is markedly reduced...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28144973/minnelide-inhibits-androgen-dependent-castration-resistant-prostate-cancer-growth-by-decreasing-expression-of-androgen-receptor-full-length-and-splice-variants
#7
Sumit Isharwal, Shrey Modi, Nivedita Arora, Charles Uhlrich, Bhuwan Giri, Usman Barlass, Ayman Soubra, Rohit Chugh, Scott M Dehm, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee, Badrinath Konety
BACKGROUND: With almost 30,000 deaths per year, prostate cancer is the second-leading cause of cancer-related death in men. Androgen Deprivation Therapy (ADT) has been the corner stone of prostate cancer treatment for decades. However, despite an initial response of prostate cancer to ADT, this eventually fails and the tumors recur, resulting in Castration Resistant Prostate Cancer (CRPC). Triptolide, a diterpene triepoxide, has been tested for its anti-tumor properties in a number of cancers for over a decade...
February 1, 2017: Prostate
https://www.readbyqxmd.com/read/28144969/high-levels-of-the-ar-v7-splice-variant-and-co-amplification-of-the-golgi-protein-coding-yipf6-in-ar-amplified-prostate-cancer-bone-metastases
#8
Erik Djusberg, Emma Jernberg, Elin Thysell, Irina Golovleva, Pia Lundberg, Sead Crnalic, Anders Widmark, Anders Bergh, Maria Brattsand, Pernilla Wikström
BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis...
February 1, 2017: Prostate
https://www.readbyqxmd.com/read/28144231/non-genomic-actions-of-the-androgen-receptor-in-prostate-cancer
#9
REVIEW
Jacky K Leung, Marianne D Sadar
Androgen receptor (AR) is a validated drug target for prostate cancer based on its role in proliferation, survival, and metastases of prostate cancer cells. Unfortunately, despite recent improvements to androgen deprivation therapy and the advent of better antiandrogens with a superior affinity for the AR ligand-binding domain (LBD), most patients with recurrent disease will eventually develop lethal metastatic castration-resistant prostate cancer (CRPC). Expression of constitutively active AR splice variants that lack the LBD contribute toward therapeutic resistance by bypassing androgen blockade and antiandrogens...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28131465/re-the-detection-of-androgen-receptor-splice-variant-7-in-plasma-derived-exosomal-rna-strongly-predicts-resistance-to-hormonal-therapy-in-metastatic-prostate-cancer-patients
#10
https://www.readbyqxmd.com/read/28129131/6bio-enhances-oligonucleotide-activity-in-cells-a-potential-combinatorial-anti-androgen-receptor-therapy-in-prostate-cancer-cells
#11
Xiaowei Zhang, Daniela Castanotto, Sangkil Nam, David Horne, Cy Stein
Approximately 15%-25% of men diagnosed with prostate cancer do not survive their disease. The American Cancer Society estimated that for the year 2016 the number of prostate cancer deaths will be 26,120. Thus, there is a critical need for novel approaches to treat this deadly disease. Using high-throughput small-molecule screening, we found that the small molecule 6-bromo-indirubin-3'-oxime (6BIO) significantly improves the targeting of antisense oligonucleotides (ASOs) delivered by gymnosis (i.e., in the absence of any transfection reagents) in both the cell cytoplasm and the nucleus...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28104311/comprehensive-profiling-of-the-androgen-receptor-in-liquid-biopsies-from-castration-resistant-prostate-cancer-reveals-novel-intra-ar-structural-variation-and-splice-variant-expression-patterns
#12
Bram De Laere, Pieter-Jan van Dam, Tom Whitington, Markus Mayrhofer, Emanuela Henao Diaz, Gert Van den Eynden, Jean Vandebroek, Jurgen Del-Favero, Steven Van Laere, Luc Dirix, Henrik Grönberg, Johan Lindberg
BACKGROUND: Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative. OBJECTIVE: To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy. DESIGN, SETTING, AND PARTICIPANTS: Peripheral blood was collected from patients with CRPC (n=30) before initiation of a new line of systemic therapy...
January 16, 2017: European Urology
https://www.readbyqxmd.com/read/28077788/androgen-receptor-splice-variants-and-prostate-cancer-from-bench-to-bedside
#13
REVIEW
Kristine M Wadosky, Shahriar Koochekpour
Therapeutic interventions for advanced prostate cancer (PCa) center on inhibiting androgen receptor (AR) and downstream signaling pathways. Resistance to androgen deprivation therapy and/or AR antagonists is inevitable and molecular mechanisms driving castration-resistant PCa (CR-PCa) primarily involve alterations in AR expression and activity. Detailed molecular biology work over the past decade, discussed at length in this review article, has revealed several AR transcripts that result from alternative splicing...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28036278/a-novel-nonsense-mutation-in-androgen-receptor-confers-resistance-to-cyp17-inhibitor-treatment-in-prostate-cancer
#14
Dong Han, Shuai Gao, Kevin Valencia, Jude Owiredu, Wanting Han, Eric de Waal, Jill A Macoska, Changmeng Cai
The standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that blocks transcriptional activity of androgen receptor (AR). However, ADT invariably leads to the development of castration-resistant PCa (CRPC) with restored activity of AR. CRPC can be further treated with CYP17 inhibitors to block androgen synthesis pathways, but most patients still relapse after a year of such treatment. The mechanisms that drive this progression are not fully understood, but AR activity, at least in a subset of cancers, appears to be restored again...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28035996/novel-nine-exon-ar-transcripts-exon-1-exon-1b-exons-2-8-in-normal-and-cancerous-breast-and-prostate-cells
#15
Dong Gui Hu, Ross A McKinnon, Julie-Ann Hulin, Peter I Mackenzie, Robyn Meech
Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2-8 but differ in exon 1 with the canonical exon 1 in isoform 1 and the variant exon 1b in isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b...
December 27, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28025139/the-rna-helicase-ddx39b-and-its-paralog-ddx39a-regulate-androgen-receptor-splice-variant-ar-v7-generation
#16
Daisuke Nakata, Shoichi Nakao, Kazuhide Nakayama, Shinsuke Araki, Yusuke Nakayama, Samuel Aparicio, Takahito Hara, Atsushi Nakanishi
Mounting evidence suggests that constitutively active androgen receptor (AR) splice variants, typified by AR-V7, are associated with poor prognosis and resistance to androgen deprivation therapy in prostate cancer patients. However, mechanisms governing the generation of AR splice variants are not fully understood. In this study, we aimed to investigate the dynamics of AR splice variant generation using the JDCaP prostate cancer model that expresses AR splice variants under androgen depletion. Microarray analysis of JDCaP xenografts before and after expression of AR splice variants suggested that dysregulation of RNA processing pathways is likely involved in AR splice variant generation...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27959342/ailanthone-targets-p23-to-overcome-mdv3100-resistance-in-castration-resistant-prostate-cancer
#17
Yundong He, Shihong Peng, Jinhua Wang, Huang Chen, Xiaonan Cong, Ang Chen, Meichun Hu, Min Qin, Haigang Wu, Shuman Gao, Liguo Wang, Xin Wang, Zhengfang Yi, Mingyao Liu
Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours...
December 13, 2016: Nature Communications
https://www.readbyqxmd.com/read/27916435/analytical-validation-of-androgen-receptor-splice-variant-7-detection-in-a-clinical-laboratory-improvement-amendments-clia-laboratory-setting
#18
Parvez M Lokhandwala, Stacy L Riel, Lisa Haley, Changxue Lu, Yan Chen, John Silberstein, Yezi Zhu, Gang Zheng, Ming-Tseh Lin, Christopher D Gocke, Alan W Partin, Emmanuel S Antonarakis, Jun Luo, James R Eshleman
Patients with castration-resistant prostate cancer (CRPC) often are treated with drugs that target the androgen receptor (AR) ligand-binding domain. Constitutively active AR splice variant 7 (AR-V7) lacks the ligand-binding domain and, if detected in circulating tumor cells, may be associated with resistance to these agents. We validated an AR-V7 assay in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Circulating tumor cells were isolated, and mRNA was reverse-transcribed into cDNA...
January 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/27915475/how-precisely-can-prostate-cancer-be-managed
#19
REVIEW
Liyan Zhuang, Matthew T Johnson
Progress has been made in applying genetic information to disease management in the postgenomic era, and precision medicine is emerging in prostate cancer management. The prostate health index, the 4-kallikrein (4K) score, and the PCA3, TMPRSS2- ERG, and Prostarix tests have potential for refining prostate cancer screening in conjunction with traditional prostate-specific antigen testing. The Confirm MDx and PCA3 tests have shown promise in identifying men who need be rebiopsied after a primary negative biopsy...
November 2016: International Neurourology Journal
https://www.readbyqxmd.com/read/27903893/identification-of-a-novel-k311-ubiquitination-site-critical-for-androgen-receptor-transcriptional-activity
#20
Urszula L McClurg, David M W Cork, Steven Darby, Claudia A Ryan-Munden, Sirintra Nakjang, Leticia Mendes Côrtes, Achim Treumann, Luke Gaughan, Craig N Robson
The androgen receptor (AR) is the main driver of prostate cancer (PC) development and progression, and the primary therapeutic target in PC. To date, two functional ubiquitination sites have been identified on AR, both located in its C-terminal ligand binding domain (LBD). Recent reports highlight the emergence of AR splice variants lacking the LBD that can arise during disease progression and contribute to castrate resistance. Here, we report a novel N-terminal ubiquitination site at lysine 311. Ubiquitination of this site plays a role in AR stability and is critical for its transcriptional activity...
November 29, 2016: Nucleic Acids Research
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