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Pten and prostate

Stephanie N David, Shanna A Arnold Egloff, Rajen Goyal, Peter E Clark, Sharon Phillips, Lan L Gellert, Omar Hameed, Giovanna A Giannico
BACKGROUND: Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI2) promotes the activity of phosphatase and tensin homolog (PTEN). Recent studies suggest that dysregulation of this signaling pathway has a role in prostate carcinogenesis. Our study aims to determine the prognostic significance of MAGI2 expression in prostate cancer. METHODS: Tissue microarrays from 51 radical prostatectomy cases including benign prostatic tissue, high grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma were constructed...
March 14, 2018: Prostate
Huimin Lu, Nicholas Bowler, Larry A Harshyne, D Craig Hooper, Shiv Ram Krishn, Senem Kurtoglu, Carmine Fedele, Qin Liu, Hsin-Yao Tang, Andrew V Kossenkov, William K Kelly, Kerith Wang, Rhonda B Kean, Paul H Weinreb, Lei Yu, Anindita Dutta, Paolo Fortina, Adam Ertel, Maria Stanczak, Flemming Forsberg, Dmitry I Gabrilovich, David W Speicher, Dario C Altieri, Lucia R Languino
Therapeutic approaches aimed at curing prostate cancer are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to therapies. Recently, we have described αvβ6, a surface receptor of the integrin family as a novel therapeutic target for prostate cancer; this epithelial-specific molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We describe a novel αvβ6-mediated signaling pathway that has profound effects on the microenvironment...
March 9, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
Jia Zhou, Jiaqi Li, Rodolfo B Serafim, Steven Ketchum, Catarina G Ferreira, Jessica C Liu, Kathryn A Coe, Brendan D Price, Timur Yusufzai
CHD1 is a conserved chromatin remodeling enzyme required for development and linked to prostate cancer in adults, yet its role in human cells is poorly understood. Here, we show that targeted disruption of the CHD1 gene in human cells leads to a defect in early double-strand break (DSB) repair via homologous recombination (HR), resulting in hypersensitivity to ionizing radiation as well as PARP and PTEN inhibition. CHD1 knockout cells show reduced H2AX phosphorylation (γH2AX) and foci formation as well as impairments in CtIP recruitment to the damaged sites...
February 26, 2018: Nucleic Acids Research
Yuqian Yan, Jian An, Yinhui Yang, Di Wu, Yang Bai, William Cao, Linlin Ma, Junhui Chen, Zhendong Yu, Yundong He, Xin Jin, Yunqian Pan, Tao Ma, Shangqian Wang, Xiaonan Hou, Saravut John Weroha, R Jeffrey Karnes, Jun Zhang, Jennifer J Westendorf, Liguo Wang, Yu Chen, Wanhai Xu, Runzhi Zhu, Dejie Wang, Haojie Huang
AKT-mTOR and androgen receptor (AR) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysine-63-chain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC3 interaction with the scaffold protein APPL1...
March 9, 2018: EMBO Molecular Medicine
W Y Mansour, P Tennstedt, J Volquardsen, C Oing, M Kluth, C Hube-Magg, K Borgmann, R Simon, C Petersen, E Dikomey, K Rothkamm
Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdown. No association was observed between PTEN-status and RAD51 expression either in-vitro or in-vivo in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation...
March 2, 2018: Scientific Reports
Jeffrey C Francis, Amy Capper, Jian Ning, Eleanor Knight, Johann de Bono, Amanda Swain
Aggressive lethal prostate cancer is characterised by tumour invasion, metastasis and androgen resistance. Understanding the mechanisms by which localised disease progresses to advanced lethal stages is key to the development of effective therapies. Here we have identified a novel role for the transcription factor, SOX9, as a driver of aggressive invasive prostate cancer. Using genetically modified mouse models, we show that increased Sox9 expression in the prostate epithelia of animals with Pten loss leads to a highly invasive phenotype and metastasis...
January 26, 2018: Oncotarget
Yuan-Chin Tsai, Wei-Yu Chen, Wassim Abou-Kheir, Tao Zeng, Juan Juan Yin, Hisham Bahmad, Yi-Chao Lee, Yen-Nien Liu
The chemokine CC motif ligand 2 (CCL2) is important in recruiting tumor-associated macrophages and is involved in the development of castration-resistance prostate cancer (CRPC) after androgen-deprivation therapy (ADT); however, the underlying mechanism remains unclear. We found that inactivation of the androgen receptor (AR) reduces a transcriptional repressor (SAM pointed domain-containing ETS transcription factor, SPDEF) of CCL2, which mediates epithelial-to-mesenchymal transition (EMT) of prostate tumor cells...
February 22, 2018: Biochimica et Biophysica Acta
Aditya Ganju, Subhash C Chauhan, Bilal Bin Hafeez, Kyle Doxtater, Manish K Tripathi, Nadeem Zafar, Murali M Yallapu, Rakesh Kumar, Meena Jaggi
BACKGROUND: Cancer progression and metastasis is profoundly influenced by protein kinase D1 (PKD1) and metastasis-associated protein 1 (MTA1) in addition to other pathways. However, the nature of regulatory relationship between the PKD1 and MTA1, and its resulting impact on cancer metastasis remains unknown. Here we present evidence to establish that PKD1 is an upstream regulatory kinase of MTA1. METHODS: Protein and mRNA expression of MTA1 in PKD1-overexpressing cells were determined using western blotting and reverse-transcription quantitative real-time PCR...
February 20, 2018: British Journal of Cancer
Tamara Jamaspishvili, David M Berman, Ashley E Ross, Howard I Scher, Angelo M De Marzo, Jeremy A Squire, Tamara L Lotan
Genomic aberrations of the PTEN tumour suppressor gene are among the most common in prostate cancer. Inactivation of PTEN by deletion or mutation is identified in ∼20% of primary prostate tumour samples at radical prostatectomy and in as many as 50% of castration-resistant tumours. Loss of phosphatase and tensin homologue (PTEN) function leads to activation of the PI3K-AKT (phosphoinositide 3-kinase-RAC-alpha serine/threonine-protein kinase) pathway and is strongly associated with adverse oncological outcomes, making PTEN a potentially useful genomic marker to distinguish indolent from aggressive disease in patients with clinically localized tumours...
February 20, 2018: Nature Reviews. Urology
Xiaofei Liu, Nianzhao Zhang, Dawei Wang, Deyu Zhu, Quan Yuan, Xiulei Zhang, Lilin Qian, Huanmin Niu, Yi Lu, Guijie Ren, Keli Tian, Huiqing Yuan
Reticulocalbin 1 (RCN1), an endoplasmic reticulum (ER)-resident Ca 2+ -binding protein, is dysregulated in cancers, but its pathophysiological roles are largely unclear. Here, we demonstrate that RCN1 is overexpressed in clinical prostate cancer (PCa) samples, associated with Cyclin B, not Cyclin D1 expression, compared to that of benign tissues in a Chinese Han population. Downregulation of endogenous RCN1 significantly suppresses PCa cell viability and arrests the cell cycles of DU145 and LNCaP cells at the S and G2/M phases, respectively...
February 17, 2018: Cancer Science
Mei Ding, Theodorus H van der Kwast, Ravi N Vellanki, Warren D Foltz, Trevor D McKee, Nahum Sonenberg, Pier Paolo Pandolfi, Marianne Koritzinsky, Bradly G Wouters
The mTOR signaling pathway is a central regulator of protein synthesis and cellular metabolism in response to the availability of energy, nutrients, oxygen, and growth factors. mTOR activation leads to phosphorylation of multiple downstream targets including the eukaryotic initiation factor 4E (eIF4E) binding proteins-1 and -2 (EIF4EBP1/4E-BP1 and EIF4EBP2/4E-BP2). These binding proteins inhibit protein synthesis, but are inactivated by mTOR to stimulate cell growth and metabolism. However, the role of these proteins in the context of aberrant activation of mTOR, which occurs frequently in cancers through loss of PTEN or mutational activation of the PI3K/AKT pathway, is unclear...
February 16, 2018: Molecular Cancer Research: MCR
Amin Allah Dashtiyan, Masood Sepehrimanesh, Nader Tanideh, Mohammad Esmaeil Afzalpour
The aim of this study was to investigate the effect of endurance training with and without vitamin E on the expression of p53 and Phosphatase and tension homolog (PTEN) tumor suppressor genes of prostate glands in male rats. For this purpose, 50 Sprague-Dawley male rats were randomly assigned into 5 groups: (1) control group (CON, n = 10), (2) sham (S, n = 10), (3) endurance training (ET, n = 10), (4) endurance training + vitamin E (ET + VE, n = 10), (5) vitamin E (VE, n = 10). Endurance training protocol was implemented for 6 weeks, 6 days per week, in accordance with the overload principle...
June 2017: Biochimie open
Dawei Mu, Gaobiao Zhou, Jianye Li, Bin Su, Heqing Guo
Ursolic acid has various pharmacological activities, and can reduce blood fat as well as having antihepatic, antitumoral, anti-inflammatory and antiviral properties. However, the pro-apoptotic mechanism by which ursolic acid influences human prostate cancer requires additional study. The aim of the present study was to assess whether ursolic acid activates the apoptosis of prostate cancer and to investigate the mechanism by which the Rho-associated protein kinase 1 (ROCK1)/phosphatase and tensin homolog (PTEN) signaling pathway performs a role in ursolic acid-mediated cofilin-1 to induce apoptosis in human prostate cancer...
March 2018: Oncology Letters
Andrea Hinsch, Meta Brolund, Claudia Hube-Magg, Martina Kluth, Ronald Simon, Christina Möller-Koop, Guido Sauter, Stefan Steurer, Andreas Luebke, Alexander Angerer, Corinna Wittmer, Emily Neubauer, Cosima Göbel, Franziska Büscheck, Sarah Minner, Waldemar Wilczak, Thorsten Schlomm, Frank Jacobsen, Till Sebastian Clauditz, Till Krech, Maria Christina Tsourlakis, Cornelia Schroeder
BACKGROUND: IDH1 mutations are oncogenic through induction of DNA damage and genome instability. They are of therapeutic interest because they confer increased sensitivity to radiation and cytotoxic therapy and hold potential for vaccination therapy. METHODS: In this study, we analyzed more than 17,000 primary prostate cancer tissues with a mutation-specific antibody for the IDH1R132H mutation. RESULTS: IDH1 mutation-specific staining was found in 42 of 15,531 (0...
February 9, 2018: World Journal of Urology
Gaelle Rondeau, Parisa Abedinpour, Adrian Chrastina, Jennifer Pelayo, Per Borgstrom, John Welsh
Treatment of mice harboring PTEN-P2 tumors in the prostate or on prostate tissue in vivo with 5-hydroxy-2-methyl-1,4-naphthoquinone, also known as plumbagin, results in tumor regression in castrated mice, but not in intact mice. This suggested that dihydrotestosterone (DHT) production in the testes may prevent cell death due to plumbagin treatment, but the underlying mechanism is not understood. We performed RNA-seq analysis on cells treated with combinations of plumbagin and DHT, and analyzed differential gene expression, to gain insight into the interactions between androgen and plumbgin...
February 9, 2018: Scientific Reports
Bastien Laperrousaz, Stephanie Porte, Sophie Gerbaud, Ville Härmä, Frédérique Kermarrec, Virginie Hourtane, Frédéric Bottausci, Xavier Gidrol, Nathalie Picollet-D'hahan
Organoid cultures in 3D matrices are relevant models to mimic the complex in vivo environment that supports cell physiological and pathological behaviors. For instance, 3D epithelial organoids recapitulate numerous features of glandular tissues including the development of fully differentiated acini that maintain apico-basal polarity with hollow lumen. Effective genetic engineering in organoids would bring new insights in organogenesis and carcinogenesis. However, direct 3D transfection on already formed organoids remains challenging...
January 31, 2018: Nucleic Acids Research
Anirban Ganguly, Hari Krishna Reddy Rachamalla, Dwaipayan Bhattacharya, Keerti Bhamidipati, Abhishek Pal, Halley Gora Ravuri, Sumana Chakrabarti, Susanta Sekhar Adhikari, Rajkumar Banerjee
Function of steroid hormone estrogen that transactivates estrogen receptor (ER) is expressed in multiple organs. Except for malignancies of gynecological organs, ER remains largely unutilized as a target to treat cancers of ER-expressing brain, prostate, skin etc. We have previously developed estrogen targeting cationic lipid molecule (ES-C10), which showed targeted killing of ER+ breast and skin cancer cells. In this study, we explored the targeting ability of ES-C10 as a ligand as well as its additive killing effect (if any), when incorporated in two different liposomes (DCME and DCDE), carrying two anticancer molecules MCIS3 and DocetaxelTM respectively...
January 29, 2018: Journal of Drug Targeting
Xin Lu, Eun-Jung Jin, Xi Cheng, Shan Feng, Xiaoying Shang, Pingna Deng, Shan Jiang, Qing Chang, Sharif Rahmy, Seema Chaudhary, Xuemin Lu, Ren Zhao, Y Alan Wang, Ronald A DePinho
SMAD4 constrains progression of Pten -null prostate cancer and serves as a common downstream node of transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) pathways. Here, we dissected the roles of TGFβ receptor II (TGFBR2) and BMP receptor II (BMPR2) using a Pten -null prostate cancer model. These studies demonstrated that the molecular actions of TGFBR2 result in both SMAD4-dependent constraint of proliferation and SMAD4-independent activation of apoptosis. In contrast, BMPR2 deletion extended survival relative to Pten deletion alone, establishing its promoting role in BMP6-driven prostate cancer progression...
December 1, 2017: Genes & Development
Mawiyah N Kimbrough-Allah, Ana C Millena, Shafiq A Khan
BACKGROUND: Transforming growth factor-β (TGF-β) acts as a tumor suppressor in normal epithelial cells but as a tumor promoter in advanced prostate cancer cells. PI3-kinase pathway mediates TGF-β effects on prostate cancer cell migration and invasion. PTEN inhibits PI3-kinase pathway and is frequently mutated in prostate cancers. We investigated possible role(s) of PTEN in TGF-β effects on proliferation and migration in prostate cancer cells. METHODS: Expression of PTEN mRNA and proteins were determined using RT-PCR and Western blotting in RWPE1 and DU145 cells...
January 16, 2018: Prostate
Maisa Yoshimoto, Olga Ludkovski, Jennifer Good, Ciro Pereira, Robert J Gooding, Jean McGowan-Jordan, Alexander Boag, Andrew Evans, Ming-Sound Tsao, Paulo Nuin, Jeremy A Squire
A variety of laboratory methods are available for the detection of deletions of tumor suppressor genes and losses of their proteins. The clinical utility of fluorescence in situ hybridization (FISH) for the identification of deletions of tumor suppressor genes has previously been limited by difficulties in the interpretation of FISH signal patterns. The first deletion FISH assays using formalin-fixed paraffin-embedded tissue sections had to deal with a significant background level of signal losses affecting nuclei that are truncated by the cutting process of slide preparation...
January 16, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
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