Prostate Cell News Volume 9.22 | Jun 15 2018

TOP STORY

A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer

Scientists identified and characterized a somatically acquired androgen receptor (AR) enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide. [Cell] Abstract | Press Release | Graphical Abstract

(Ranked by impact factor of the journal)

Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer

Researchers identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss was enriched in metastatic castration-resistant prostate cancer relative to clinically localized disease and characterized by focal tandem duplications that lead to increased gene fusions and marked differential gene expression. [Cell] Abstract | Press Release | Graphical Abstract

Aberrant FGFR Tyrosine Kinase Signaling Enhances the Warburg Effect by Reprogramming LDH Isoform Expression and Activity in Prostate Cancer

Investigators reported that fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase reprogramed the energy metabolism of prostate cancer cells by regulating expression of lactate dehydrogenase (LDH) isozymes. FGFR1 increased LDHA stability through tyrosine phosphorylation and reduced LDHB expression by promoting its promoter methylation, thereby shifting cell metabolism from oxidative phosphorylation to aerobic glycolysis. [Cancer Res] Abstract | Full Article

Novel Trifluoromethylated Enobosarm Analogues with Potent Anti-Androgenic Activity In Vitro and Tissue Selectivity In Vivo.

In vitro, the analogues SK33 and SK51 showed very potent antiandrogenic activity, monitored using LNCaP/androgen receptor (AR)-Luciferase cells where growth, PSA and luciferase activity were used as AR activity measurements. These compounds were 10-fold more potent than bicalutamide and 100-fold more potent than enobosarm within the LNCaP model. [Mol Cancer Ther] Abstract | Full Article

AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells

Researchers demonstrated the antineoplastic activity of a potent, isoform selective and hydrolytically stable aldo-keto reductase 1C3 (AKR1C3) inhibitor (E)-3-(4-(3-methylbut-2-en-1-yl)-3-(3-phenylpropanamido)phenyl)acrylic acid (KV-37) which reduced prostate cancer cell growth in vitro and in vivo, and sensitized castration-resistant prostate cancer cell lines towards the anti-tumor effects of enzalutamide. [Mol Cancer Ther] Abstract

Inhibition of ANO1/TMEM16A Induces Apoptosis in Human Prostate Carcinoma Cells by Activating TNF-α Signaling

The authors showed that silencing or inhibition of endogenous ANO1 inhibited cell growth, induced apoptosis and upregulated TNF-α expression in prostate cancer PC-3 cells. Enhancement of TNF-α signaling by ANO1 knockdown lead to upregulation of phosphorylated Fas-associated protein with death domain and caspase activation. [Cell Death Dis] Full Article

Without 1α-Hydroxylation, the Gene Expression Profile of 25(OH)D₃ Treatment Overlaps Deeply with That of 1,25(OH)₂D₃ in Prostate Cancer Cells

Investigators found that at a physiological concentration, 25(OH)D₃ (25D3), the precursor of 1,25D3 and an inactive form of vitamin D because of its much weaker binding activity to the vitamin D receptor compared with 1,25D3, had a gene expression profile similar to that of 1,25D3 in prostate cancer LNCaP cells. [Sci Rep] Full Article

Extracellular Vesicles with Altered Tetraspanin CD9 and CD151 Levels Confer Increased Prostate Cell Motility and Invasion

Researchers aimed to determine whether extracellular vessicles (EVs) from prostate cells with altered CD9 and CD151 expression could influence cellular behavior and increase the metastatic capabilities of non-tumorigenic prostate cells. Addition of EVs from RWPE1 cells with reduced CD9 or increased CD151 abundance resulted in increased invasion of RWPE1 cells, and increased migration in the case of high CD151 abundance. [Sci Rep] Full Article

Small RNA-Induced INTS6 Gene Up-Regulation Suppresses Castration-Resistant Prostate Cancer Cells by Regulating β-Catenin Signaling

The putative tumor suppressor, INTS6, was activated by introducing a promoter-targeted small RNA into castration-resistant prostate cancer cells. Following gene activation, cell proliferation and motility were suppressed in vitro. Downregulation of Wnt/β-catenin signaling was observed during the activation period, and the impairment of β-catenin degradation reversed the tumor suppressor effects of INTS6. [Cell Cycle] Abstract

Application of Mixture Design Response Surface Methodology for Combination Chemotherapy in PC-3 Human Prostate Cancer Cells

Scientists modeled combination drug therapy in PC-3 human prostate cancer cells using mixture design response surface methodology (MDRSM), a statistical technique designed to optimize compositions to achieve the most desirable result. MDRSM combinations were compared with combination index data from the Chou-Talalay method and were found to coincide. [Mol Pharmacol] Abstract | Full Article

Effect of ASP6432, a Novel Type 1 Lysophosphatidic Acid Receptor Antagonist, on Urethral Function and Prostate Cell Proliferation

ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}-1,3-thiazole-4-carbonyl)-3-ethyl-2,2-dioxo-2λ6-diazathian-1-ide), exhibited potent and selective antagonistic activity against type 1 lysophosphatidic acid receptor (LPA1) in cells expressing LPA receptor subtypes. In human prostate stromal cells, ASP6432 significantly and concentration-dependently suppressed LPA-induced bromodeoxyuridine incorporation. [J Pharmacol Exp Ther] Abstract | Full Article

Intratumor Heterogeneity in Prostate Cancer

The authors present a comprehensive review of the various studies addressing intra-tumor heterogeneity in prostate cancer and in the context of that seen in other solid tumors. They discuss the impact of heterogeneity on clinical decision-making in treating both primary and metastatic lesions and how our understanding of this heterogeneity might help in developing better diagnostic tools and biomarkers and in guiding the selection of better therapeutic strategies. [Urol Oncol] Abstract

Visit our reviews page to see a complete list of reviews in the prostate cell research field.

U.K. Creates £2.5B Investment Program to Help Startups Grow

The U.K. has set up a £2.5 billion ($3.6 billion) patient capital program. The fund is part of an initiative to help British biotechs grow into standalone midsized businesses, rather than sell up at the first sign of a takeover bid from overseas. [Fierce Biotech] Press Release

ITUS Corporation Announces First Commercial Focus for Cchek^™ Will Be Prostate Cancer

ITUS Corporation announced that it has chosen prostate cancer as the first commercial focus for its Cchek^™, non-invasive liquid biopsy cancer detection platform. [ITUS Corporation] Press Release

Astellas Announces Launch of XTANDI^® Tablets in Japan for the Treatment of Castration-Resistant Prostate Cancer

Astellas Pharma Inc. announced that it launched 40 mg XTANDI^® tablets and 80 mg XTANDI^® tablets in Japan for the treatment of castration-resistant prostate cancer, which add additional dosage forms to the previously available 40 mg XTANDI^® Capsules. XTANDI^® is an oral androgen receptor signaling inhibitor. [Astellas Pharma Inc.] Press Release

Trials Begin of a Saliva Test for Prostate Cancer

Doctors have begun a trial of a simple saliva test that aims to spot the top 10% of men who are most at risk of developing prostate cancer. The test draws on more than 150 DNA markers to identify the 10% of men who have nearly a threefold greater risk of the disease than the general population, and the 1% of men with a sixfold greater risk. [The Guardian] Press Release

New Zealand Appoints First Female Chief Scientific Adviser

The New Zealand government has appointed biochemist Juliet Gerrard as its next chief scientific adviser — the first woman to hold the position. [Nature News] Editorial

Bill to Encourage Generic-Drug Development Passes a Key Hurdle

A key Senate committee voted to advance legislation that aims to spur the development of new generic drugs and in turn, lower drug prices. [Stat News] Editorial

Sexual Harassment Is Rife in the Sciences, Finds Landmark US Study

The analysis concludes that policies to fight the problem are ineffective because they are set up to protect institutions, not victims — and that universities, funding agencies, scientific societies and other organizations must take stronger action. [Nature News] Editorial

House Bill Gives NIH a 3% Boost in 2019, to $38.3 Billion

A draft bill released by a House of Representatives spending panel would give the National Institutes of Health (NIH) in Bethesda, Maryland, a $1.25 billion raise in 2019, to $38.3 billion. That is 3% more than this year’s level and $4.1 billion more than President Donald Trump’s administration had requested. [ScienceInsider] Editorial

NEW The American Society for Cell Biology (ASCB) Annual Meeting 2018
December 8-12, 2018
San Diego, California, United States

Visit our events page to see a complete list of events in the community.

NEW Postdoctoral Fellow – Cancer Research (Princess Margaret Cancer Centre)

Postdoctoral Positions – Ribosome Modifications (University of Copenhagen)

Research Fellow – Prostate Cancer (Sechenov University)

Postdoctoral Position – Steroid Hormone Production and Signaling (University of Rochester Medical Center)

Postdoctoral Positions – Transcriptional/Epigenetic Regulation in Cancer Progression (UT Health San Antonio)

Postdoctoral Fellow/Research Scientists – Prostate Cancer Research (Institute of Oncology Research – Universita della Svizzera Italiana)

Postdoctoral Position – Drug Discovery for Advance Prostate Cancer (Lerner Research Institute – Cleveland Clinic)

Research Associate – Computational Biology (University College London)

Academic Position – Cancer Research (Cedars-Sinai Medical Center)

Postdoctoral Fellow – Prostate Cancer (Moffitt Cancer Center)

Postdoctoral Associate – Prostate Research (Baylor College of Medicine)

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