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Selective androgen receptor mediators

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https://www.readbyqxmd.com/read/29032351/testosterone-induced-modulation-of-peroxisomal-morphology-and-peroxisome-related-gene-expression-in-brown-trout-salmo-trutta-f-fario-primary-hepatocytes
#1
Célia Lopes, Fernanda Malhão, Cláudia Guimarães, Ivone Pinheiro, José F Gonçalves, L Filipe C Castro, Eduardo Rocha, Tânia V Madureira
Disruption of androgenic signaling has been linked to possible cross-modulation with other hormone-mediated pathways. Therefore, our objective was to explore effects caused by testosterone - T (1, 10 and 50μM) in peroxisomal signaling of brown trout hepatocytes. To study the underlying paths involved, several co-exposure conditions were tested, with flutamide - F (anti-androgen) and ICI 182,780 - ICI (anti-estrogen). Molecular and morphological approaches were both evaluated. Peroxisome proliferator-activated receptor alpha (PPARα), catalase and urate oxidase were the selected targets for gene expression analysis...
September 28, 2017: Aquatic Toxicology
https://www.readbyqxmd.com/read/28978635/novel-selective-agents-for-the-degradation-of-androgen-receptor-variants-to-treat-castration-resistant-prostate-cancer
#2
Suriyan Ponnusamy, Christopher C Coss, Thirumagal Thiyagarajan, Kate Watts, Dong-Jin Hwang, Yali He, Luke A Selth, Iain J McEwan, Charles B Duke, Jayaprakash Pagadala, Geetika Singh, Robert W Wake, Christopher Ledbetter, Wayne D Tilley, Tudor Moldoveanu, James T Dalton, Duane D Miller, Ramesh Narayanan
Androgen receptor (AR) mediates the growth of prostate cancer (PCa) throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced PCa requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARDs) that markedly reduce the activity of wildtype and splice variant isoforms of AR at sub-micromolar doses...
October 4, 2017: Cancer Research
https://www.readbyqxmd.com/read/28974548/selective-androgen-receptor-modulator-rad140-inhibits-the-growth-of-androgen-estrogen-receptor-positive-breast-cancer-models-with-a-distinct-mechanism-of-action
#3
Ziyang Yu, Suqin He, Dannie Wang, Hitisha K Patel, Chris P Miller, Jeff Brown, Gary Hattersley, Jamal C Saeh
PURPOSE: Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) breast cancer cells and were used to treat breast cancer eliciting favorable response. The present study evaluates the activity and efficacy of the oral selective AR modulator (SARM) RAD140 in in vivo and in vitro models of AR/ER+ breast cancer. EXPERIMENTAL DESIGN: A series of in vitro assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity...
October 3, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28900498/correlation-between-erg-fusion-protein-and-androgen-receptor-expression-by-immunohistochemistry-in-prostate-possible-role-in-diagnosis-and-therapy
#4
Amir Hassan Navaei, Beatriz A Walter, Vanessa Moreno, Svetlana D Pack, Peter Pinto, Maria J Merino
Background: Recent discovery of gene rearrangements have brought a new look to the molecular pathogenesis of cancer. Gene fusions occur in nearly 60% of prostate adenocarcinoma, being the TMPRSS2-ERG one of the most common. Evidence supports the role of ERG fusion in tumorigenesis, progression and invasion via effecting pathways such as WNT, MYC, uPA, PI3K/AKT/PTEN, RAS/RAF/MAPF, NKX3.1, GST-pi and androgen receptor (AR) mediated signaling. Most of the ERG fusions involve 5'-partners androgen responsive. Therefore, we aimed to evaluate AR and ERG fusion protein expression on prostate tissue to find clinicopathological applications and possible role in therapy...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28891793/regulation-of-the-glucocorticoid-receptor-via-a-bet-dependent-enhancer-drives-antiandrogen-resistance-in-prostate-cancer
#5
Neel Shah, Ping Wang, John Wongvipat, Wouter R Karthaus, Wassim Abida, Joshua Armenia, Shira Rockowitz, Yotam Drier, Bradley E Bernstein, Henry W Long, Matthew L Freedman, Vivek K Arora, Deyou Zheng, Charles L Sawyers
In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals...
September 11, 2017: ELife
https://www.readbyqxmd.com/read/28831645/effects-of-cytokines-derived-from-cancer-associated-fibroblasts-on-androgen-synthetic-enzymes-in-estrogen-receptor-negative-breast-carcinoma
#6
Kyoko Kikuchi, Keely May McNamara, Yasuhiro Miki, Ju-Yeon Moon, Man Ho Choi, Fumiya Omata, Minako Sakurai, Yoshiaki Onodera, Yoshiaki Rai, Yasuyo Ohi, Yasuaki Sagara, Minoru Miyashita, Takanori Ishida, Noriaki Ohuchi, Hironobu Sasano
PURPOSE: The tumor microenvironment plays pivotal roles in promotion of many malignancies. Cancer-associated fibroblasts (CAFs) have been well-known to promote proliferation, angiogenesis, and metastasis but mechanistic understanding of tumor-stroma interactions is not yet complete. Recently, estrogen synthetic enzymes were reported to be upregulated by co-culture with stromal cells in ER positive breast carcinoma (BC) but effects of co-culture on androgen metabolism have not been extensively examined...
August 22, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28826481/a-comprehensive-analysis-of-coregulator-recruitment-androgen-receptor-function-and-gene-expression-in-prostate-cancer
#7
Song Liu, Sangeeta Kumari, Qiang Hu, Dhirodatta Senapati, Varadha Balaji Venkadakrishnan, Dan Wang, Adam D DePriest, Simon E Schlanger, Salma Ben-Salem, Malyn May Valenzuela, Belinda Willard, Shaila Mudambi, Wendy M Swetzig, Gokul M Das, Mojgan Shourideh, Shahriah Koochekpour, Sara Moscovita Falzarano, Cristina Magi-Galluzzi, Neelu Yadav, Xiwei Chen, Changshi Lao, Jianmin Wang, Jean-Noel Billaud, Hannelore V Heemers
Standard treatment for metastatic prostate cancer (CaP) prevents ligand-activation of androgen receptor (AR). Despite initial remission, CaP progresses while relying on AR. AR transcriptional output controls CaP behavior and is an alternative therapeutic target, but its molecular regulation is poorly understood. Here, we show that action of activated AR partitions into fractions that are controlled preferentially by different coregulators. In a 452-AR-target gene panel, each of 18 clinically relevant coregulators mediates androgen-responsiveness of 0-57% genes and acts as a coactivator or corepressor in a gene-specific manner...
August 18, 2017: ELife
https://www.readbyqxmd.com/read/28789969/tissue-control-of-androgen-action-the-ups-and-downs-of-androgen-receptor-expression
#8
REVIEW
Irene Hunter, Colin W Hay, Bianca Esswein, Kate Watt, Iain J McEwan
The hormone testosterone plays crucial roles during male development and puberty and throughout life, as an anabolic regulator of muscle and bone structure and function. The actions of testosterone are mediated, primarily, through the androgen receptor, a member of the nuclear receptor superfamily. The androgen receptor gene is located on the X-chromosome and receptor levels are tightly controlled both at the level of transcription of the gene and post-translationally at the protein level. Sp1 has emerged as the major driver of expression of the androgen receptor gene, while auto-regulation by androgens is associated with both positive and negative regulation in a possible cell-selective manner...
August 5, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28757136/iminoenamine-based-novel-androgen-receptor-antagonist-exhibited-anti-prostate-cancer-activity-in-androgen-independent-prostate-cancer-cells-through-inhibition-of-akt-pathway
#9
S Divakar, K Saravanan, P Karthikeyan, R Elancheran, S Kabilan, K K Balasubramanian, Rajlakshmi Devi, J Kotoky, M Ramanathan
Treatment by androgen receptor (AR) antagonists is one of the regimens for prostate cancer. The prolonged treatment with AR antagonist leads to the expression of point mutation in the ligand binding domain of the AR. This point mutation causes resistance to AR antagonist by converting them into an agonist. The T887A mutated AR was frequently expressed in androgen independent prostate cancer (AIPC) patients. Through literature survey and molecular modelling, we have identified a novel AR antagonist having a bulky β-iminoenamine BF2 complex scaffold...
September 25, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28711501/comparing-the-androgenic-and-estrogenic-properties-of-progestins-used-in-contraception-and-hormone-therapy
#10
COMPARATIVE STUDY
Renate Louw-du Toit, Meghan S Perkins, Janet P Hapgood, Donita Africander
Progestins used in endocrine therapies bind to multiple steroid receptors and are associated with several side-effects. It is thus important to understand the relationship between steroid receptor cross-reactivity and the side-effect profile of progestins. In cell lines that express negligible levels of steroid receptors, we report for the first time the binding affinities, potencies and efficacies of selected progestins from different generations determined in parallel. We show that the progestins bind to the androgen receptor (AR) with similar affinities to each other and progesterone, while none bind estrogen receptor (ER)-β, and only norethisterone acetate, levonorgestrel and gestodene bind ERα...
September 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28708672/artemisinin-disrupts-androgen-responsiveness-of-human-prostate-cancer-cells-by-stimulating-the-26s-proteasome-mediated-degradation-of-the-androgen-receptor-protein
#11
Andrea M Steely, Jamin A Willoughby, Shyam N Sundar, Vasiliki I Aivaliotis, Gary L Firestone
Androgen receptor (AR) expression and activity is highly linked to the development and progression of prostate cancer and is a target of therapeutic strategies for this disease. We investigated whether the antimalarial drug artemisinin, which is a sesquiterpene lactone isolated from the sweet wormwood plant Artemisia annua, could alter AR expression and responsiveness in cultured human prostate cancer cell lines. Artemisinin treatment induced the 26S proteasome-mediated degradation of the receptor protein, without altering AR transcript levels, in androgen-responsive LNCaP prostate cancer cells or PC-3 prostate cancer cells expressing exogenous wild-type AR...
July 13, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28639228/role-of-20-hydroxyeicosatetraenoic-acid-20-hete-in-androgen-mediated-cell-viability-in-prostate-cancer-cells
#12
Cecilia Colombero, Daniela Papademetrio, Paula Sacca, Eduardo Mormandi, Elida Alvarez, Susana Nowicki
20-Hydroxyeicosatetraenoic acid (20-HETE) is generated intracellularly through the ω-hydroxylation of arachidonic acid by the cytochrome P450 (in humans, CYP4A11 and CYP4F2). 20-HETE induces mitogenic responses in different cancer cells. The aim of this study was to analyze how 20-HETE impacts cell survival, proliferation, and apoptosis in prostate cancer cells. Incubation of the human androgen-sensitive cells (LNCaP) with 1-10 μM HET0016 (a selective inhibitor of 20-HETE synthesis) reduced cell viability by 49*-64%* (*p < 0...
August 2017: Hormones & Cancer
https://www.readbyqxmd.com/read/28607032/characterization-of-an-androgen-responsive-ornithine-decarboxylase-related-protein-in-mouse-kidney
#13
Kristian M Silander, Päivi Pihlajamaa, Biswajyoti Sahu, Olli A Jänne, Leif C Andersson
We have investigated and characterized a novel ornithine decarboxylase (ODC) related protein (ODCrp) also annotated as gm853. ODCrp shows 41% amino acid sequence identity with ODC and 38% with ODC antizyme inhibitor 1 (AZIN1). The Odcrp gene is selectively expressed in the epithelium of proximal tubuli of mouse kidney with higher expression in males than in females. Like Odc in mouse kidney, Odcrp is also androgen responsive with androgen receptor (AR)-binding loci within its regulatory region. ODCrp forms homodimers but does not heterodimerize with ODC...
August 31, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28591577/androgen-receptor-deregulation-drives-bromodomain-mediated-chromatin-alterations-in-prostate-cancer
#14
Alfonso Urbanucci, Stefan J Barfeld, Ville Kytölä, Harri M Itkonen, Ilsa M Coleman, Daniel Vodák, Liisa Sjöblom, Xia Sheng, Teemu Tolonen, Sarah Minner, Christoph Burdelski, Kati K Kivinummi, Annika Kohvakka, Steven Kregel, Mandeep Takhar, Mohammed Alshalalfa, Elai Davicioni, Nicholas Erho, Paul Lloyd, R Jeffrey Karnes, Ashley E Ross, Edward M Schaeffer, Donald J Vander Griend, Stefan Knapp, Eva Corey, Felix Y Feng, Peter S Nelson, Fahri Saatcioglu, Karen E Knudsen, Teuvo L J Tammela, Guido Sauter, Thorsten Schlomm, Matti Nykter, Tapio Visakorpi, Ian G Mills
Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect...
June 6, 2017: Cell Reports
https://www.readbyqxmd.com/read/28590577/non-neural-androgen-receptors-affect-sexual-differentiation-of-brain-and-behavior
#15
REVIEW
D A Monks, A Swift-Gallant
Although gonadal testosterone is the principal endocrine factor that promotes masculine traits in mammals, the development of a male phenotype requires local production of both androgenic and estrogenic signals within target tissues. Much of our knowledge concerning androgenic components of testosterone signaling in sexual differentiation comes from studies of androgen receptor (Ar) loss of function mutants. Here, we review these studies of loss of Ar function and of AR overexpression either globally or selectively in the nervous system of mice...
June 7, 2017: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/28588757/identification-of-neuron-selective-androgen-receptor-inhibitors
#16
Maya Otto-Duessel, Ben Yi Tew, Steven Vonderfecht, Roger Moore, Jeremy O Jones
AIM: To identify neuron-selective androgen receptor (AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness. METHODS: Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell type-selective AR inhibitors...
May 26, 2017: World Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28504114/a-shortened-tamoxifen-induction-scheme-to-induce-creer-recombinase-without-side-effects-on-the-male-mouse-skeleton
#17
Ferran Jardí, Michaël R Laurent, Vanessa Dubois, Rougin Khalil, Ludo Deboel, Dieter Schollaert, Ludo Van Den Bosch, Brigitte Decallonne, Geert Carmeliet, Frank Claessens, Dirk Vanderschueren
The selective estrogen receptor modulator tamoxifen exerts estrogen agonistic or antagonistic actions on several tissues, including bone. The off-target effects of tamoxifen are one of the most widely recognized pitfalls of tamoxifen-inducible Cre recombinases (CreERs), potentially confounding the phenotypic findings. Still, the validation of tamoxifen induction schemes that minimize the side effects of the drug has not been addressed. Here, we compared the side effects on the skeleton and other androgen-responsive targets of a shortened tamoxifen regimen (2 doses of 190 mg/kg body weight by oral gavage) to a standard protocol (4 doses) and determined their efficiency in inducing CreER-mediated gene deletion...
May 11, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28439080/ets-related-gene-mediated-androgen-receptor-aggregation-and-endoplasmic-reticulum-stress-in-prostate-cancer-development
#18
Taduru L Sreenath, Shiela S Macalindong, Natallia Mikhalkevich, Shashwat Sharad, Ahmed Mohamed, Denise Young, Talaibek Borbiev, Charles Xavier, Rishita Gupta, Muhammad Jamal, Kevin Babcock, Shyh-Han Tan, Marja T Nevalainen, Albert Dobi, Gyorgy Petrovics, Isabell A Sesterhenn, Inger L Rosner, Charles J Bieberich, Peter Nelson, Valeri Vasioukhin, Shiv Srivastava
Mechanistic studies of deregulated ERG in prostate cancer and other cancers continue to enhance its role in cancer biology and its utility as a biomarker and therapeutic target. Here, we show that ERG, through its physical interaction with androgen receptor, induces AR aggregation and endoplasmic reticulum stress in the prostate glands of ERG transgenic mice. Histomorphological alterations and the expression of ER stress sensors Atf6, Ire1α, Perk, their downstream effectors Grp78/BiP and eIF2α in ERG transgenic mouse prostate glands indicate the presence of chronic ER stress...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28428441/selective-glucocorticoid-receptor-modulators-sgrms-delay-castrate-resistant-prostate-cancer-growth
#19
Jacob Kach, Tiha M Long, Phillip Selman, Eva Y Tonsing-Carter, Maria A Bacalao, Ricardo R Lastra, Larischa de Wet, Shane Comiskey, Marc Gillard, Calvin VanOpstall, Diana C West, Wen-Ching Chan, Donald Vander Griend, Suzanne D Conzen, Russell Z Szmulewitz
Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here, we report that two novel nonsteroidal and highly selective GR modulators (SGRM), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer and slow CRPC progression...
August 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28427194/alternative-rna-splicing-of-the-meaf6-gene-facilitates-neuroendocrine-prostate-cancer-progression
#20
Ahn R Lee, Yinan Li, Ning Xie, Martin E Gleave, Michael E Cox, Colin C Collins, Xuesen Dong
Although potent androgen receptor pathway inhibitors (ARPI) improve overall survival of metastatic prostate cancer patients, treatment-induced neuroendocrine prostate cancer (t-NEPC) as a consequence of the selection pressures of ARPI is becoming a more common clinical issue. Improved understanding of the molecular biology of t-NEPC is essential for the development of new effective management approaches for t-NEPC. In this study, we identify a splice variant of the MYST/Esa1-associated factor 6 (MEAF6) gene, MEAF6-1, that is highly expressed in both t-NEPC tumor biopsies and neuroendocrine cell lines of prostate and lung cancers...
April 25, 2017: Oncotarget
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