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https://www.readbyqxmd.com/read/29142193/pten-is-a-protein-phosphatase-that-targets-active-ptk6-and-inhibits-ptk6-oncogenic-signaling-in-prostate-cancer
#1
Darren J Wozniak, Andre Kajdacsy-Balla, Virgilia Macias, Susan Ball-Kell, Morgan L Zenner, Wenjun Bie, Angela L Tyner
PTEN activity is often lost in prostate cancer. We show that the tyrosine kinase PTK6 (BRK) is a PTEN substrate. Phosphorylation of PTK6 tyrosine 342 (PY342) promotes activation, while phosphorylation of tyrosine 447 (PY447) regulates auto-inhibition. Introduction of PTEN into a PTEN null prostate cancer cell line leads to dephosphorylation of PY342 but not PY447 and PTK6 inhibition. Conversely, PTEN knockdown promotes PTK6 activation in PTEN positive cells. Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342...
November 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/29141866/prostate-specific-membrane-antigen-cleavage-of-vitamin-b9-stimulates-oncogenic-signaling-through-metabotropic-glutamate-receptors
#2
Charalambos Kaittanis, Chrysafis Andreou, Haley Hieronymus, Ninghui Mao, Catherine A Foss, Matthias Eiber, Gregor Weirich, Palak Panchal, Anuradha Gopalan, Juan Zurita, Samuel Achilefu, Gabriela Chiosis, Vladimir Ponomarev, Markus Schwaiger, Brett S Carver, Martin G Pomper, Jan Grimm
Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer. Its expression correlates inversely with survival and increases with tumor grade. However, the biological role of PSMA has not been explored, and its role in prostate cancer remained elusive. Filling this gap, we demonstrate that in prostate cancer, PSMA initiates signaling upstream of PI3K through G protein-coupled receptors, specifically via the metabotropic glutamate receptor (mGluR). PSMA's carboxypeptidase activity releases glutamate from vitamin B9 and other glutamated substrates, which activate mGluR I...
November 15, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29137428/pten-loss-is-associated-with-prostate-cancer-recurrence-and-alterations-in-tumor-dna-methylation-profiles
#3
Milan S Geybels, Min Fang, Jonathan L Wright, Xiaoyu Qu, Marina Bibikova, Brandy Klotzle, Jian-Bing Fan, Ziding Feng, Elaine A Ostrander, Peter S Nelson, Janet L Stanford
Background: Prostate cancer (PCa) with loss of the tumor suppressor gene PTEN has an unfavorable prognosis. DNA methylation profiles associated with PTEN loss may provide further insights into the mechanisms underlying these more aggressive, clinically relevant tumors. Methods: The cohort included patients with clinically localized PCa. Samples taken from the primary tumor were used to determine PTEN genomic deletions using FISH, and to analyze epigenome-wide DNA methylation profiles...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29134654/pten-loss-and-activation-of-k-ras-and-%C3%AE-catenin-cooperate-to-accelerate-prostate-tumourigenesis
#4
Matthew T Jefferies, Adam C Cox, Boris Y Shorning, Valerie Meniel, David Griffiths, Howard G Kynaston, Matthew J Smalley, Alan R Clarke
Aberrant phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and WNT signalling are emerging as key events in the multistep nature of prostate tumourigenesis and progression. Here, we report a compound prostate cancer murine model in which these signalling pathways cooperate to produce a more aggressive prostate cancer phenotype. Using Cre-LoxP technology and the probasin promoter, we combined the loss of Pten (Pten(fl/fl) ), to activate the PI3K signalling pathway, with either dominant stabilized β-catenin [Catnb(+/lox(ex3)) ] or activated K-RAS (K-Ras(+/V12) ) to aberrantly activate WNT and MAPK signalling, respectively...
December 2017: Journal of Pathology
https://www.readbyqxmd.com/read/29123407/association-of-pten-expression-with-biochemical-recurrence-in-prostate-cancer-results-based-on-previous-reports
#5
Haijie Xie, Bin Xie, Chunyu Liu, Jun Wang, Yong Xu
Purpose: Among men, prostate cancer (PCa) is one of the most commonly diagnosed cancers and the leading cause of cancer death worldwide. Phosphatase and tension homolog (PTEN) acts as a negative regulator of the phosphatidylinositol 3-kinase (PIK3)/Akt pathway and suppresses tumor progression. Meanwhile, PTEN is frequently deleted in PCa. Identifying the specific molecular markers of biochemical recurrence (BCR) in PCa patients is critical in clinical practice. Our systematic review summarizes the evidence about the PTEN expression and BCR rate in PCa patients...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29121168/%C3%AE-tocopherol-inhibits-the-development-of-prostate-adenocarcinoma-in-prostate-specific-pten-mice
#6
Hong Wang, Xu Yang, Anna Liu, Guocan Wang, Maarten C Bosland, Chung S Yang
The PTEN/PI3K/AKT axis plays a critical role in regulating cell growth, differentiation and survival. Activation of this signaling pathway is frequently found in human cancers. Our previous studies demonstrated that δ-tocopherol (δ-T) attenuates the activation of AKT by growth factor in prostate cancer cell lines, leading to inhibition of proliferation and induction of apoptosis. Herein, we investigated whether δ-T inhibits the development of prostate adenocarcinoma in prostate-specific Pten-/- (Ptenp-/-) mice in which the activation of AKT is the major driving force for tumorigenesis...
November 7, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29113189/the-oncogenic-transcription-factor-erg-represses-the-transcription-of-the-tumour-suppressor-gene-pten-in-prostate-cancer-cells
#7
Patricia Adamo, Sean Porazinski, Shavanthi Rajatileka, Samantha Jumbe, Rachel Hagen, Man-Kim Cheung, Ian Wilson, Michael R Ladomery
The oncogene ETS-related gene (ERG) encodes a transcription factor with roles in the regulation of haematopoiesis, angiogenesis, vasculogenesis, inflammation, migration and invasion. The ERG oncogene is activated in >50% of prostate cancer cases, generally through a gene fusion with the androgen-responsive promoter of transmembrane protease serine 2. Phosphatase and tensin homologue (PTEN) is an important tumour suppressor gene that is often inactivated in cancer. ERG overexpression combined with PTEN inactivation or loss is often associated with aggressive prostate cancer...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29101113/treatment-of-advanced-prostate-cancer-a-review-of-current-therapies-and-future-promise
#8
Semini Sumanasuriya, Johann De Bono
Despite many recent advances in the therapy for metastatic castration-resistant prostate cancer (mCRPC), the disease remains incurable, although men suffering from this disease are living considerably longer. In this review, we discuss the current treatment options available for this disease, such as taxane-based chemotherapy, the novel hormone therapies abiraterone and enzalutamide, and treatments such as radium-223 and sipuleucel-T. We also highlight the need for ongoing research in this field, because, despite numerous recent advances, the prognosis for mCRPC remains poor...
November 3, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29100379/gambogic-acid-inhibits-thioredoxin-activity-and-induces-ros-mediated-cell-death-in-castration-resistant-prostate-cancer
#9
Hong Pan, Keith H Jansson, Michael L Beshiri, JuanJuan Yin, Lei Fang, Supreet Agarwal, Holly Nguyen, Eva Corey, Ying Zhang, Jie Liu, HuiTing Fan, HongSheng Lin, Kathleen Kelly
Advanced prostate cancer (PrCa) is treated with androgen deprivation therapy, and although there is usually a significant initial response, recurrence arises as castrate resistant prostate cancer (CRPC). New approaches are needed to treat this genetically heterogeneous, phenotypically plastic disease. CRPC with combined homozygous alterations to PTEN and TP53 comprise about 30% of clinical samples. We screened eleven traditional Chinese medicines against a panel of androgen-independent Pten/Tp53 null PrCa-derived cell lines and identified gambogic acid (GA) as a highly potent growth inhibitor...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29084195/c10orf116-gene-copy-number-loss-in-prostate-cancer-clinicopathological-correlations-and-prognostic-significance
#10
Jie Meng, Li-Hui Wang, Chun-Lin Zou, Sheng-Ming Dai, Jian Zhang, Yi Lu
BACKGROUND Prostate cancer (PCa) is the second most commonly diagnosed cancer in males worldwide. This study aimed to identify differentially expressed genes and to investigate the potential correlation between gene abnormalities and clinical features in PCa to evaluate disease progression and prognosis. MATERIAL AND METHODS A total of 4 independent microarrays of PCa patients from the Oncomine database were used to identify differences in expression of genes contributing to cancer progression. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis was used to evaluate the mRNA expression of the target in human prostate cancer cells...
October 30, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29069829/the-mir-486-5p-plays-a-causative-role-in-prostate-cancer-through-negative-regulation-of-multiple-tumor-suppressor-pathways
#11
Yang Yang, Changwei Ji, Suhan Guo, Xin Su, Xiaozhi Zhao, Shiwei Zhang, Guangxiang Liu, Xuefeng Qiu, Qing Zhang, Hongqian Guo, Huimei Chen
MicroRNAs have been broadly implicated in cancer, but their exact function and mechanism in carcinogenesis remain poorly understood. Aberrant miR-486-5p expression is frequently found in human cancers. Here we showed a significant overexpression of miR-486-5p in prostate cancer compared with that in normal tissue and cells, and we proposed that altered expression of miR-486-5p in the prostate contributed to prostate cancer. Firstly, miR-486-5p inhibition expression reduced prostate cancercell proliferation, migration, and colonization in vitro and prostate tumor development in vivo...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29057879/deletion-of-3p13-14-locus-spanning-foxp1-to-shq1-cooperates-with-pten-loss-in-prostate-oncogenesis
#12
Haley Hieronymus, Phillip J Iaquinta, John Wongvipat, Anuradha Gopalan, Rajmohan Murali, Ninghui Mao, Brett S Carver, Charles L Sawyers
A multigenic locus at 3p13-14, spanning FOXP1 to SHQ1, is commonly deleted in prostate cancer and lost broadly in a range of cancers but has unknown significance to oncogenesis or prognosis. Here, we report that FOXP1-SHQ1 deletion cooperates with PTEN loss to accelerate prostate oncogenesis and that loss of component genes correlates with prostate, breast, and head and neck cancer recurrence. We demonstrate that Foxp1-Shq1 deletion accelerates prostate tumorigenesis in mice in combination with Pten loss, consistent with the association of FOXP1-SHQ1 and PTEN loss observed in human cancers...
October 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/29056325/pten-regulates-pi-3-4-p2-signaling-downstream-of-class-i-pi3k
#13
Mouhannad Malek, Anna Kielkowska, Tamara Chessa, Karen E Anderson, David Barneda, Pınar Pir, Hiroki Nakanishi, Satoshi Eguchi, Atsushi Koizumi, Junko Sasaki, Véronique Juvin, Vladimir Y Kiselev, Izabella Niewczas, Alexander Gray, Alexandre Valayer, Dominik Spensberger, Marine Imbert, Sergio Felisbino, Tomonori Habuchi, Soren Beinke, Sabina Cosulich, Nicolas Le Novère, Takehiko Sasaki, Jonathan Clark, Phillip T Hawkins, Len R Stephens
The PI3K signaling pathway regulates cell growth and movement and is heavily mutated in cancer. Class I PI3Ks synthesize the lipid messenger PI(3,4,5)P3. PI(3,4,5)P3 can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P2. The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P3 3-phosphatase, limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P2 3-phosphatase, both in vitro and in vivo. PTEN is a major PI(3,4)P2 phosphatase in Mcf10a cytosol, and loss of PTEN and INPP4B, a known PI(3,4)P2 4-phosphatase, leads to synergistic accumulation of PI(3,4)P2, which correlated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells...
November 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29051161/prostate-cancer-cells-express-more-androgen-receptor-ar-following-androgen-deprivation-improving-recognition-by-ar-specific-t-cells
#14
Brian M Olson, Melissa Gamat, Joseph Seliski, Thomas Sawicki, Justin Jeffery, Leigh Ellis, Charles G Drake, Jamey Weichert, Douglas G McNeel
Androgen deprivation is the primary therapy for recurrent prostate cancer, and agents targeting the androgen receptor (AR) pathway continue to be developed. Because androgen-deprivation therapy (ADT) has immmunostimulatory effects as well as direct antitumor effects, AR-targeted therapies have been combined with other anticancer therapies, including immunotherapies. Here, we sought to study whether an antigen-specific mechanism of resistance to ADT (overexpression of the AR) may result in enhanced AR-specific T-cell immune recognition, and whether this might be strategically combined with an antitumor vaccine targeting the AR...
October 19, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29029453/pten-loss-detection-in-prostate-cancer-comparison-of-pten-immunohistochemistry-and-pten-fish-in-a-large-retrospective-prostatectomy-cohort
#15
Tamara L Lotan, Asmus Heumann, Sebastian Dwertmann Rico, Jessica Hicks, Kristen Lecksell, Christina Koop, Guido Sauter, Thorsten Schlomm, Ronald Simon
PTEN deletion is an established prognostic biomarker in prostate cancer. We compared PTEN immunohistochemistry (IHC) and PTEN fluorescence in situ hybridization (FISH) in the largest existing radical prostatectomy cohort with clinical follow-up data. There was high concordance between IHC and FISH: 93% (3098/3330) of tumors with intact PTEN IHC showed absence of PTEN gene deletion and 66% (720/1087) of cases with PTEN protein loss by IHC showed PTEN gene deletion by FISH. 84% (447/533) of cases with PTEN homozygous gene deletion had PTEN protein loss by IHC...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29029032/foxa1-expression-is-a-strong-independent-predictor-of-early-psa-recurrence-in-erg-negative-prostate-cancers-treated-by-radical-prostatectomy
#16
Maria Christina Tsourlakis, Agapi Eleftheriadou, Annegret Stender, Philipp Weigand, Katharina Grupp, Claudia Hube-Magg, Martina Kluth, Cornelia Schroeder, Stefan Steurer, Andrea Hinsch, Andreas Luebke, Alexander Angerer, Corinna Wittmer, Emily Friedrich, Cosima Göbel, Franziska Büscheck, Hans Heinzer, Markus Graefen, Ronald Simon, Guido Sauter, Waldemar Wilczak, Sarah Minner, Thorsten Schlomm, Frank Jacobsen
FOXA1 is a transcription factor involved in androgen signaling with relevance for lineage specific gene expression of the prostate. The expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancer specimens. Results were compared to tumor phenotype, biochemical recurrence, androgen receptor expression, ERG status and other recurrent genomic alterations. FOXA1 expression was detectable in 97.6% of 8,227 interpretable cancers and considered strong in 28.5%, moderate in 46...
September 26, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29024573/targeting-mta1-hif-1%C3%AE-signaling-by-pterostilbene-in-combination-with-histone-deacetylase-inhibitor-attenuates-prostate-cancer-progression
#17
Nasir A Butt, Avinash Kumar, Swati Dhar, Agnes M Rimando, Israh Akhtar, John C Hancock, Janice M Lage, Charles R Pound, Jack R Lewin, Christian R Gomez, Anait S Levenson
The metastasis-associated protein 1(MTA1)/histone deacetylase (HDAC) unit is a cancer progression-related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer (PCa). In our previous studies, we found a significantly increased MTA1 expression in a prostate-specific Pten-null mouse model. We also demonstrated that stilbenes, namely resveratrol and pterostilbene (Pter), affect MTA1/HDAC signaling, including deacetylation of tumor suppressors p53 and PTEN. In this study, we examined whether inhibition of MTA1/HDAC using combination of Pter and a clinically approved HDAC inhibitor, SAHA (suberoylanilide hydroxamic acid, vorinostat), which also downregulates MTA1, could block prostate tumor progression in vivo...
November 2017: Cancer Medicine
https://www.readbyqxmd.com/read/29021651/microrna-21-could-be-a-molecular-marker-to-predict-the-recurrence-of-nonmuscle-invasive-bladder-cancer
#18
Nilay Mitash, Shalini Agnihotri, Swasti Tiwari, Vinita Agrawal, Anil Mandhani
INTRODUCTION: High relapse rate of nonmuscle invasive bladder cancer (NMIBC) is a major challenge. Overexpression of microRNA-21 (miR-21) which targets phosphatase and tensin homolog (PTEN), a gene associated with malignancy, has been reported in the bladder tumor tissue compared to normal mucosa by us and others. We have tested whether miR-21 levels in bladder mucosa could predict tumor recurrence. METHODS: In a prospective cohort setting, tumor tissues and normal bladder mucosa (NBM) were taken from BC patients during transurethral resection of bladder tumor...
October 2017: Indian Journal of Urology: IJU: Journal of the Urological Society of India
https://www.readbyqxmd.com/read/28977864/gene-polymorphisms-in-the-pi3k-akt-mtor-signaling-pathway-contribute-to-prostate-cancer-susceptibility-in-chinese-men
#19
Ting Liu, Abulajiang Gulinaer, Xiaoli Shi, Feng Wang, Hengqing An, Wenli Cui, Qiaoxin Li
In this hospital-based case-control study of 413 prostate cancer (PCa) cases and 807 cancer-free controls, we investigated the role of functional single nucleotide polymorphisms (SNPs) of pivotal genes in the PI3K/AKT/mTOR pathway. We genotyped 17 SNPs in mTOR, Raptor, AKT1, AKT2, PTEN, and K-ras and found that 4 were associated with PCa susceptibility. Among the variants, the homozygote variant CC genotype of mTOR rs17036508 C>T were associated with higher PCa risk than the wild TT genotypes (adjusted OR = 3...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28945110/effects-of-obesity-on-the-regulation-of-macrophage-population-in-the-prostate-tumor-microenvironment
#20
G C Galván, C B Johnson, R S Price, M A Liss, C A Jolly, L A deGraffenried
Obesity is associated with a greater risk of prostate cancer mortality. However, the mechanisms connecting obesity to the progression of prostate cancer remain unknown. This study determined the impact of obesity on macrophage recruitment and tumor-associated macrophage (TAM) polarization in the prostate tumor microenvironment, since a high concentration of TAMs in tumors has been linked to progression in prostate cancer. We utilized an in vitro model in which pre-adipocytes, prostate cancer cells, and macrophages were exposed to sera from obese or nonobese men, or conditioned media generated under obese or nonobese conditions...
September 25, 2017: Nutrition and Cancer
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