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Pten and prostate

Sofia Lisanti, David S Garlick, Kelly G Bryant, Michele Tavecchio, Gordon B Mills, Yiling Lu, Andrew V Kossenkov, Louise C Showe, Lucia R Languino, Dario C Altieri
Protein homeostasis, or proteostasis is required for mitochondrial function, but its role in cancer is controversial. Here, we show that transgenic mice expressing the mitochondrial chaperone, TRAP1 in the prostate develop epithelial hyperplasia and cellular atypia. When examined on a Pten+/- background, a common alteration in human prostate cancer, TRAP1 transgenic mice showed accelerated incidence of invasive prostatic adenocarcinoma, characterized by increased cell proliferation and reduced apoptosis, in situ...
October 17, 2016: Journal of Biological Chemistry
Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
Sarah A Altınoğlu, Ming Wang, Kathleen Q Li, Yuyang Li, Qiaobing Xu
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor, mutated or inactive in a large percentage of human cancers. Restoring PTEN activity in cancer cells through gene therapy has shown to inhibit cell growth and induce apoptosis, particularly in cells with a PTEN deficiency. Gene therapy, however, comes with some inherent risks such as triggering an immune response and permanent off target effects. Nanoparticle assisted protein delivery could mitigate these liabilities while maintaining therapeutic integrity...
October 17, 2016: Biomaterials Science
Kuo-Cheng Huang, Andrew Evans, Bryan Donnelly, Tarek A Bismar
SPINK1 is proposed as potential prognostic marker in prostate cancer (PCA). However, its relation to PTEN and ERG in localized PCA remains unclear. The study population consisted of two independent cohorts of men treated by radical prostatectomy for localized PCA (discovery n = 218 and validation n = 129). Patterns of association between SPINK1 and each of ERG and PTEN were evaluated by immunohistochemistry and fluorescence in situ hybridization. Associations between SPINK1 expression and various pathologic parameters and clinical outcome were also investigated...
October 13, 2016: Pathology Oncology Research: POR
Surya Narayan Rath, Debasrita Das, V Badireenath Konkimalla, Sukanta Kumar Pradhan
Solid tumor is generally observed in tissues of epithelial or endothelial cells of lung, breast, prostate, pancreases, colorectal, stomach, and bladder, where several genes transcription is regulated by the microRNAs (miRNAs). Argonaute (AGO) protein is a family of protein which assists in miRNAs to bind with mRNAs of the target genes. Hence, study of the binding mechanism between AGO protein and miRNAs, and also with miRNAs-mRNAs duplex is crucial for understanding the RNA silencing mechanism. In the current work, 64 genes and 23 miRNAs have been selected from literatures, whose deregulation is well established in seven types of solid cancer like lung, breast, prostate, pancreases, colorectal, stomach, and bladder cancer...
September 2016: Genomics & Informatics
Benhong Zhou, Jing Wang, Guohua Zheng, Zhenpeng Qiu
Urolithins are bioactive ellagic acid-derived metabolites produced by human colonic microflora. Although previous studies have demonstrated the cytotoxicity of urolithins, the effect of urolithins on miRNAs is still unclear. In this study, the suppressing effects of methylated urolithin A (mUA) on cell viability in human prostate cancer DU145 cells was investigated. mUA induced caspase-dependent cell apoptosis, mitochondrial depolarization and down-regulation of Bcl-2/Bax ratio. The results showed that upon exposure to mUA, miR-21 expression was decreased and the expression of PTEN and Pdcd4 protein was elevated...
October 8, 2016: Food and Chemical Toxicology
Pei Jing, Shousong Cao, Shuangli Xiao, Xiaoqin Zhang, Siyun Ke, Famin Ke, Xin Yu, Li Wang, Shurong Wang, Yuling Luo, Zhirong Zhong
The peptide aptamer DUP-1 targets prostate-specific membrane antigen (PSMA)-negative cells, while the RNA aptamer A10-3.2 targets PSMA-positive prostate cancer cells. Moreover, the tumor-suppressor gene phosphatase and tensin homolog (PTEN) and the chemotherapeutic agent doxorubicin (DOX) effectively inhibit prostate cancer, and a recombinant adenovirus (Ad5) mediates high gene transfer efficiency. Here, we design a dual-aptamer modified tumor targeting gene and DOX delivery system mediated by recombinant adenovirus (A10-3...
October 6, 2016: Cancer Letters
Young A Yoo, Meejeon Roh, Anum F Naseem, Barbara Lysy, Mohamed M Desouki, Kenji Unno, Sarki A Abdulkadir
Identification of defined cell populations with stem/progenitor properties is key for understanding prostate development and tumorigenesis. Here we show that the polycomb repressor protein Bmi1 marks a population of castration-resistant luminal epithelial cells enriched in the mouse proximal prostate. We employ lineage tracing to show that these castration-resistant Bmi1-expressing cells (or CARBs) are capable of tissue regeneration and self-renewal. Notably, CARBs are distinct from the previously described luminal castration-resistant Nkx3...
October 5, 2016: Nature Communications
Sheng Hu, Qiang Zhou, Wan-Rui Wu, Yi-Xing Duan, Zhi-Yong Gao, Yuan-Wei Li, Qiang Lu
Deoxypodophyllotoxin (DPPT) is extracted and separated from citrus-related plants, including Podophyllum (P.) peltatum, P. pleianthum, P. emodi (also called P. hexandrum) and Diphylleia grayi. DPPT has significant antitumor and antiviral activity. However, due to its strong toxicity and side effects, its use is limited in practical applications. The in vitro antitumor efficacy of DPPT on human prostate cancer (PCa) cells remains to be determined. The present study investigated the anticancer effect of DPPT on human PCa cells and its potential mechanism...
October 2016: Oncology Letters
Wen-Tao Gai, Da-Peng Yu, Xin-Sheng Wang, Pei-Tao Wang
Ursolic acid is a type of pentacyclic triterpene compound with multiple pharmacological activities including cancer resistance, protection from liver injury, antisepsis, anti-inflammation and antiviral activity. The present study aimed to investigate the anticancer effect of ursolic acid. Ursolic acid activates cell apoptosis and its pro-apoptotic mechanism remains to be fully elucidated. Cell Counting kit-8 assays, flow cytometric analysis and analysis of caspase-3 and caspase-9 activity were used to estimate the anticancer effect of ursolic acid on DU145 prostate cancer cells...
October 2016: Oncology Letters
Vincenzo N Talesa, Ivana Ferri, Guido Bellezza, Harold D Love, Angelo Sidoni, Cinzia Antognelli
BACKGROUND: Glyoxalase 2 (Glo2), together with glyoxalase 1 (Glo1), forms the main scavenging system of methylglyoxal, a potent pro-apoptotic agent mainly generated by glycolysis. An increased rate of glycolysis is a well known signature of cancer cells. As a survival strategy, Glo1 is overexpressed in many human malignant cells, including prostate cancer (PCa), where it plays a crucial role in progression. No information is available on the role of Glo2 in the same ambit. PCa is the most common malignancy affecting men in the western world...
October 3, 2016: Prostate
Liana B Guedes, Jeffrey J Tosoian, Jessica Hicks, Ashley E Ross, Tamara L Lotan
PURPOSE: Men with intermediate risk prostate cancer have widely variable outcomes, with some suggesting that active surveillance or less invasive therapies (brachytherapy or focal therapy) may be appropriate for some men with Gleason Score 3+4=7 disease. Molecular markers may help further distinguish prostate cancers with aggressive behavior. Here, we tested whether loss of the PTEN tumor suppressor in 3+4=7 tumor biopsies is associated with adverse pathology at prostatectomy. MATERIALS AND METHODS: We queried prostate needle biopsies from 2000-2014 with a maximum Gleason score of 3+4=7 followed by prostatectomy...
September 27, 2016: Journal of Urology
Dingxiao Zhang, Kevin Lin, Yue Lu, Kiera Rycaj, Yi Zhong, Hsueh-Ping Chao, Tammy Calhoun-Davis, Jianjun Shen, Dean G Tang
: : Elucidating the cell of origin of cancer has great significance in stratifying patients into appropriate treatment groups and for developing novel targeted therapies. Early studies demonstrate that only stem-like basal cells in the normal human prostate (NHP) can function as the cell of origin for prostate cancer (PCa). Here, we show that the organoids derived from bulk NHP luminal cells can also be tumorigenically transformed. We further show that the WIT medium, which is used to culture human mammary epithelial progenitor cells, when combined with the ROCK inhibitor, can readily propagate a population of progenitor-like cells from the primary NHP luminal cell isolates...
September 29, 2016: Stem Cells Translational Medicine
Seong M Kim, Saurabh G Roy, Bin Chen, Tiffany M Nguyen, Ryan J McMonigle, Alison N McCracken, Yanling Zhang, Satoshi Kofuji, Jue Hou, Elizabeth Selwan, Brendan T Finicle, Tricia T Nguyen, Archna Ravi, Manuel U Ramirez, Tim Wiher, Garret G Guenther, Mari Kono, Atsuo T Sasaki, Lois S Weisman, Eric O Potma, Bruce J Tromberg, Robert A Edwards, Stephen Hanessian, Aimee L Edinger
Oncogenic mutations drive anabolic metabolism, creating a dependency on nutrient influx through transporters, receptors, and macropinocytosis. While sphingolipids suppress tumor growth by downregulating nutrient transporters, macropinocytosis and autophagy still provide cancer cells with fuel. Therapeutics that simultaneously disrupt these parallel nutrient access pathways have potential as powerful starvation agents. Here, we describe a water-soluble, orally bioavailable synthetic sphingolipid, SH-BC-893, that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways...
September 26, 2016: Journal of Clinical Investigation
Hannah Nip, Altaf A Dar, Sharanjot Saini, Melissa Colden, Shahryari Varahram, Harshika Chowdhary, Soichiro Yamamura, Yozo Mitsui, Yuichiro Tanaka, Taku Kato, Yutaka Hashimoto, Marisa Shiina, Priyanka Kulkarni, Pritha Dasgupta, Mitsuho Imai-Sumida, Z Laura Tabatabai, Kirsten Greene, Guoren Deng, Rajvir Dahiya, Shahana Majid
Prostate carcinogenesis involves alterations in several signaling pathways, the most prominent being the PI3K/AKT pathway. This pathway is constitutively active and drives prostate cancer (PCa) progression to advanced metastatic disease. PTEN, a critical tumor and metastasis suppressor gene negatively regulates cell survival, proliferation, migration and angiogenesis via the PI3K/Akt pathway. PTEN is mutated, downregulated/dysfunctional in many cancers and its dysregulation correlates with poor prognosis in PCa...
September 15, 2016: Oncotarget
Nicholas H Farina, Areg Zingiryan, Jacqueline A Akech, Cody J Callahan, Huimin Lu, Janet L Stein, Lucia R Languino, Gary S Stein, Jane B Lian
While decades of research have identified molecular pathways inducing and promoting stages of prostate cancer malignancy, studies addressing dynamic changes of cancer-related regulatory factors in a prostate tumor progression model are limited. Using the TRAMP mouse model of human prostate cancer, we address mechanisms of deregulation for the cancer-associated transcription factors, Runx1 and Runx2 by identifying microRNAs with reciprocal expression changes at six time points during 33 weeks of tumorigenesis...
September 13, 2016: Oncotarget
Tamara L Lotan, Wei Wei, Carlos L Morais, Sarah T Hawley, Ladan Fazli, Antonio Hurtado-Coll, Dean Troyer, Jesse K McKenney, Jeffrey Simko, Peter R Carroll, Martin Gleave, Raymond Lance, Daniel W Lin, Peter S Nelson, Ian M Thompson, Lawrence D True, Ziding Feng, James D Brooks
BACKGROUND: PTEN is the most commonly deleted tumor suppressor gene in primary prostate cancer (PCa) and its loss is associated with poor clinical outcomes and ERG gene rearrangement. OBJECTIVE: We tested whether PTEN loss is associated with shorter recurrence-free survival (RFS) in surgically treated PCa patients with known ERG status. DESIGN SETTING AND PARTICIPANTS: A genetically validated, automated PTEN immunohistochemistry (IHC) protocol was used for 1275 primary prostate tumors from the Canary Foundation retrospective PCa tissue microarray cohort to assess homogeneous (in all tumor tissue sampled) or heterogeneous (in a subset of tumor tissue sampled) PTEN loss...
June 2016: European Urology Focus
Santosh Gupta, Jing Li, Gabor Kemeny, Rhonda L Bitting, Joshua Beaver, Jason Somarelli, Kathryn E Ware, Simon Gregory, Andrew J Armstrong
PURPOSE: Beyond enumeration, circulating tumor cells (CTCs) can provide genetic information from metastatic cancer that may facilitate a greater understanding of tumor biology and enable a precision medicine approach. EXPERIMENTAL DESIGN: CTCs and paired leukocytes from men with metastatic castration-resistant prostate cancer (mCRPC) were isolated from blood through red cell lysis, CD45 depletion, and flow sorting based on EpCAM/CD45 expression. We next performed whole genomic copy number analysis of CTCs and matched patient leukocytes (germline) using array-based comparative genomic hybridization (aCGH) from 16 men with mCRPC, including longitudinal and sequential CTCs aCGH analyses in the context of enzalutamide therapy...
September 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Wenying Ren, Raghav Joshi, Paul Mathew
: The bone-conserved metastatic phenotype of prostate cancer is a prototype of non-random metastatic behavior. Adhesion of prostate cancer cells to fibronectin via the integrin α5 (ITGA5) has been proposed as a candidate bone marrow niche localization mechanism. We hypothesized that the mechanisms whereby ITGA5 regulates the adhesion-mediated survival of prostate cancer cells will define novel therapeutic approaches. ITGA5 shRNA reduced expression of BCL-2 family members and induced apoptosis in PC-3 cells...
September 2, 2016: Molecular Cancer Research: MCR
Martuza Sarwar, Julius Semenas, Regina Miftakhova, Athanasios Simoulis, Brian Robinson, Anette Gjörloff Wingren, Nigel P Mongan, David M Heery, Heather Johnsson, Per-Anders Abrahamsson, Nishtman Dizeyi, Jun Luo, Jenny L Persson
One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Kα inhibitor highlight the potential of PIP5K1α as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1α in tumor specimens from PCa patients...
August 31, 2016: Oncotarget
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