scholarly journals NVP-BEZ235 Enhances Radiosensitivity of Human Prostate Cancer Cells but Acts as a Radioprotector to Normal Prostate Cells

2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Sechaba Maleka ◽  
Antonio Serafin ◽  
Roswita Hamunyela ◽  
Mogammad Hamid ◽  
Daniel Achel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Specific Inhibitor ◽  
Cellular Heterogeneity ◽  
Radiation Response ◽  
Human Prostate ◽  
Normal Prostate ◽  
Prostate Cell

Targeted therapy for prostate cancer may offer potential improvement over current conventional therapies because of its specificity. Although conventional treatments are effective, they are not always curative, andhave several limitations. In prostate cancer, activation of the epidermal growth factor receptor (EGFR) and the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways have been implicatedin tumorigenesis, and resistance to both conventional and targeted anticancer therapies. Single-target therapies may fail due to cellular heterogeneity. Concomitant targeting of EGFR and PI3K/mTOR cell signaling components may enhance the efficacy of radiotherapy. In this study, the effect of an EGFR inhibitor (AG-1478) and a dual inhibitor of PI3K and mTOR (NVP-BEZ235) on the radiation response of a human prostate carcinoma cell line (DU145) and a normal prostate cell line (1542N) was investigated, using the colony forming assay. Treatment ofDU145 cells with AG-1478 and NVP-BEZ235, either singly or in combination, resulted in a slight radiosensitisation of DU145 cells. Neither AG-1478 nor a cocktail of both inhibitors had an effect on the radiation response of the 1542N cell line. Interestingly, NVP-BEZ235 significantly protected 1542N cells from radiation-induced cell death. These data suggest that a specific inhibitor of PI3K and mTOR (NVP-BEZ235) could potentially be effective as a radio-protector.

Cerebellar Degeneration-Related Autoantigen 1 (CDR1) Gene Expression in Prostate Cancer Cell Lines

2014 ◽  
Vol 29 (3) ◽  
pp. 288-290 ◽  
Author(s):  
Michele Salemi ◽  
Filippo Fraggetta ◽  
Antonio Galia ◽  
Pietro Pepe ◽  
Laura Cimino ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Cerebellar Degeneration ◽  
Normal Prostate ◽  
Prostate Cell ◽  
Prostate Cell Line ◽  
Normal Prostate Cell

Prostate cancer (PCa) is the most frequent cancer among men in many developing countries, and the second leading cause of cancer-related death in men. A genetic component has been implicated in PCa onset and development. The cerebellar degeneration-related autoantigen 1 ( CDR1) gene, mapping in Xq26-q27.2, is expressed in cerebrum, cerebellum, heart, lung, liver, and kidney. In addition, CDR1 expression has been detected in neuroblastoma, renal carcinoma cell lines, and other cancer cell lines. In this study, we investigated the expression of the CDR1 gene in the LNCaP and PC-3 PCa cell lines, and in the PNT1A normal prostate cell line. CDR1 mRNA expression was evaluated by qRT-PCR. We found that the CDR1 gene was overexpressed in the LNCaP and PC-3 PCa cell lines as compared with the PNT1A normal prostate cell line. These data suggest that CDR1 could be a new biomarker for PCa identification.

USP2a is an oncogenic isopeptidase and a potential target in prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14522-14522
Author(s):  
C. Priolo ◽  
D. Tang ◽  
M. Brahmandam ◽  
B. Benassi ◽  
E. Sicinska ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nude Mice ◽  
Fatty Acid Synthase ◽  
Chemotherapeutic Agents ◽  
Human Prostate ◽  
Wild Type ◽  
Normal Prostate ◽  
Prostate Cell

14522 Background: De-ubiquitinating enzymes (isopeptidases) remove ubiquitin side chains prior to degradation by the proteosome thus stabilizing their protein targets. We have identified a novel androgen regulated isopeptidase, USP2a, and demonstrated that it binds and prolongs the half-life of fatty acid synthase (FAS), a key enzyme in lipid metabolism of tumor cells. Methods: We determined whether USP2a has oncogenic properties in vitro and in vivo. Wild-type and catalytically inactive USP2a were introduced in immortalized normal prostate epithelial cells (AR-iPrECs). Clonogenicity assays and apoptosis induction by chemotherapeutic agents were performed on these cells. Anti-USP2a siRNA were transfected in normal and transformed (LNCaP, DU145 and PC-3) prostate cell lines. Oncogenicity in vivo was shown by s.c. injection of NIH3T3-USP2a cells in nude mice. Furthermore, USP2a mRNA expression and gene microarrays were tested in 52 human prostate adenocarcinomas. Results: Wild-type USP2a overexpression in AR-iPrEC cells resulted in a significant increase in number and size of colonies compared to those obtained in parental cells. Growth in soft agar was significantly enhanced as well. Silencing of USP2a in LNCAP and DU145 cells resulted in a strong apoptotic effect, evaluated by FACS analysis and cleaved-PARP expression. The role of this isopeptidase in apoptosis regulation was confirmed on AR-iPrEC-USP2a cells, that showed resistance to apoptosis induced by cisplatin and taxol. Importantly, USP2a overexpression was able to transform NIH3T3 cells, generating greater than or equal to 0.5 cm subcutaneous tumors in 12/12 nude mice within 3 weeks, while none of the negative controls grew. USP2a mRNA was overexpressed in 39% of human prostate cancers, showing 1.6–104 (median 5.48) fold induction relative to normal tissues by qRT-PCR. Gene expression profiling of the same tumors revealed specific signatures in USP2a-overexpressing tumors. Conclusions: Our results demonstrate that USP2a behaves as an oncogene in vitro and in vivo and is overexpressed in organ-confined prostate cancer. These data strongly suggest that this isopeptidase is a potential drug target in prostate cancer. [Table: see text]

Deleted in cancer 1: Search for a function in prostate cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16095-e16095
Author(s):  
J. Hirsch ◽  
T. Nelius ◽  
C. Pfarr ◽  
W. De Riese ◽  
I. Wieland ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Factor ◽  
Cell Line ◽  
Cell Lines ◽  
Expression Profiling ◽  
Ectopic Expression ◽  
Mrna Levels ◽  
Normal Prostate ◽  
Prostate Cell ◽  
Growth Inhibitory

e16095 Background: Deleted In Cancer 1 (DICE1/INTS6) gene was recently identified to colocalize with the microsatellite marker D13S284 in 13q14.3, a region frequently affected by allelic deletion in many solid tumors including prostate cancer (PrCa). DICE1 missense mutations have been previously detected in PrCa cell line LNCap, and reduced DICE1 expression appears to be associated with CpG promoter hypermethylation in PrCa cells. DICE1 is a highly conserved nuclear protein suggesting its involvement in DNA repair, transcription, or RNA splicing. In mouse, the DICE1 homologue interferes with the response to insulin-like growth factor 1 and suppresses anchorage-independent growth of transformed mouse cells. The totality of these results suggests that DICE1 is a tumor suppressor gene and insist on the need to better characterize DICE1 function in PrCa. Methods: Expression of DICE1 was evaluated by Northern Blot in PrCa cell lines LNCap, DU145, PC3, PC3ml and CPTX1532 and compared to expression level in normal prostate cell line NPTX1532. DICE1 growth inhibitory effects were analyzed by colony formation assay on PC3 and DU145 cells transfected with DICE1 expression plasmid or control vector. Apoptosis was assessed by visualization of genomic DNA fragmentation on agarose gel. PCR arrays (SABiosciences) were used to identify specific signaling pathways modulated in response to DICE1 expression. Results: Markedly decreased DICE1 mRNA levels were detected in PrCa cell lines LNCap, DU145, PC3 and PC3ml as well as CPTX1532 as compared to NPTX1532, a cell line derived from normal prostate tissue. Ectopic expression of DICE1 cDNA in DU145 and PC3 cells substantially suppressed their ability to form colonies in vitro. This growth inhibition was not due to immediate induction of apoptosis suggesting growth suppression by other pathways. Expression profiling identified multiple pathways, such as Wnt, Hedgehog, PI-3 Kinase, NFκB and Insulin pathways, regulated in response to ectopic DICE1 expression. Furthermore, various transcription factors including Fos, Jun, CEBPA and PPAR-γ were up-regulated in response to DICE1. Conclusions: These results clearly illustrate the growth inhibitory ability of DICE1 in PrCa. Expression profiling links DICE1 function to growth factor signaling and cell-cell communication. No significant financial relationships to disclose.

In vitro dorsal root ganglia and human prostate cell line interaction: Redefining perineural invasion in prostate cancer

The Prostate ◽  
2001 ◽  
Vol 49 (3) ◽  
pp. 213-223 ◽  
Author(s):  
Gustavo E. Ayala ◽  
Thomas M. Wheeler ◽  
H. David Shine ◽  
Monika Schmelz ◽  
Ana Frolov ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Perineural Invasion ◽  
Human Prostate ◽  
Prostate Cell ◽  
Prostate Cell Line

Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line

2003 ◽  
Vol 129 (3) ◽  
pp. 175-182 ◽  
Author(s):  
Albert A. Geldof ◽  
Marian A.B.D. Plaizier ◽  
Ilse Duivenvoorden ◽  
Marieke Ringelberg ◽  
Richard T. Versteegh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Line ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Human Prostate Cancer Cell

scholarly journals Metabolic Roles of Androgen Receptor and Tip60 in Androgen-Dependent Prostate Cancer

2020 ◽  
Vol 21 (18) ◽  
pp. 6622
Author(s):  
Kah Ni Tan ◽  
Vicky M. Avery ◽  
Catalina Carrasco-Pozo
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cell Fate ◽  
Tricarboxylic Acid Cycle ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Normal Prostate ◽  
Calcium Calmodulin Dependent ◽  
Metabolic Regulators

Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. It is well known that cancer cells rewire their metabolic pathways in order to sustain aberrant proliferation. Growing evidence demonstrates that the AR and Tip60 modulate key metabolic processes to promote the survival of prostate cancer cells, in addition to their classical roles. AR activation enhances glucose metabolism, including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation, as well as lipid metabolism in prostate cancer. The AR also interacts with other metabolic regulators, including calcium/calmodulin-dependent kinase kinase 2 and mammalian target of rapamycin. Several studies have revealed the roles of Tip60 in determining cell fate indirectly by modulating metabolic regulators, such as c-Myc, hypoxia inducible factor 1α (HIF-1α) and p53 in various cancer types. Furthermore, Tip60 has been shown to regulate the activity of key enzymes in gluconeogenesis and glycolysis directly through acetylation. Overall, both the AR and Tip60 are master metabolic regulators that mediate cellular energy metabolism in prostate cancer, providing a framework for the development of novel therapeutic targets in androgen-dependent prostate cancer.

scholarly journals Differential Actions of Estrogen Receptor α and β via Nongenomic Signaling in Human Prostate Stem and Progenitor Cells

Endocrinology ◽  
2019 ◽  
Vol 160 (11) ◽  
pp. 2692-2708 ◽  
Author(s):  
Shyama Majumdar ◽  
Jaqueline C Rinaldi ◽  
Neha R Malhotra ◽  
Lishi Xie ◽  
Dan-Ping Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Estrogen Receptor ◽  
Progenitor Cells ◽  
Mapk Signaling ◽  
Human Prostate ◽  
Estrogen Signaling ◽  
Stem Cell Population ◽  
Normal Prostate ◽  
Phosphorylated Akt ◽  
Stem And Progenitor Cells

Abstract Human prostate stem and progenitor cells express estrogen receptor (ER)α and ERβ and exhibit proliferative responses to estrogens. In this study, membrane-initiated estrogen signaling was interrogated in human prostate stem/progenitor cells enriched from primary epithelial cultures and stem-like cell lines from benign and cancerous prostates. Subcellular fractionation and proximity ligation assays localized ERα and ERβ to the cell membrane with caveolin-1 interactions. Exposure to 17β-estradiol (E2) for 15 to 60 minutes led to sequential phosphorylation of signaling molecules in MAPK and AKT pathways, IGF1 receptor, epidermal growth factor receptor, and ERα, thus documenting an intact membrane signalosome that activates diverse downstream cascades. Treatment with an E2–dendrimer conjugate or ICI 182,870 validated E2-mediated actions through membrane ERs. Overexpression and knockdown of ERα or ERβ in stem/progenitor cells identified pathway selectivity; ERα preferentially activated AKT, whereas ERβ selectively activated MAPK cascades. Furthermore, prostate cancer stem-like cells expressed only ERβ, and brief E2 exposure activated MAPK but not AKT cascades. A gene subset selectively regulated by nongenomic E2 signaling was identified in normal prostate progenitor cells that includes BGN, FOSB, FOXQ1, and MAF. Membrane-initiated E2 signaling rapidly modified histone methyltransferases, with MLL1 cleavage observed downstream of phosphorylated AKT and EZH2 phosphorylation downstream of MAPK signaling, which may jointly modify histones to permit rapid gene transcription. Taken together, the present findings document ERα and ERβ membrane-initiated signaling in normal and cancerous human prostate stem/progenitor cells with differential engagement of downstream effectors. These signaling pathways influence normal prostate stem/progenitor cell homeostasis and provide novel therapeutic sites to target the elusive prostate cancer stem cell population.

scholarly journals Gene expression analysis of human prostate cell lines with and without tumor metastasis suppressor CD82

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Pushpaja Dodla ◽  
Vanitha Bhoopalan ◽  
Sok Kean Khoo ◽  
Cindy Miranti ◽  
Suganthi Sridhar
Keyword(s):  
Gene Expression ◽  
Cell Line ◽  
Cell Lines ◽  
Differentially Expressed Genes ◽  
Tumor Metastasis ◽  
Human Prostate ◽  
Metastasis Suppressor ◽  
Data Sets ◽  
Prostate Cell ◽  
Prostate Cell Lines

Abstract Background Tetraspanin CD82 is a tumor metastasis suppressor that is known to down regulate in various metastatic cancers. However, the exact mechanism by which CD82 prevents cancer metastasis is unclear. This study aims to identify genes that are regulated by CD82 in human prostate cell lines. Methods We used whole human genome microarray to obtain gene expression profiles in a normal prostate epithelial cell line that expressed CD82 (PrEC-31) and a metastatic prostate cell line that does not express CD82 (PC3). Then, siRNA silencing was used to knock down CD82 expression in PrEC-31 while CD82 was re-expressed in PC3 to acquire differentially-expressed genes in the respective cell line. Results Differentially-expressed genes with a P < 0.05 were identified in 3 data sets: PrEC-31 (+CD82) vs PrEC-31(−CD82), PC3–57 (+CD82) vs. PC3-5 V (−CD82), and PC3–29 (+CD82) vs. PC3-5 V (−CD82). Top 25 gene lists did not show overlap within the data sets, except (CALB1) the calcium binding protein calbindin 1 which was significantly up-regulated (2.8 log fold change) in PrEC-31 and PC3–29 cells that expressed CD82. Other most significantly up-regulated genes included serine peptidase inhibitor kazal type 1 (SPINK1) and polypeptide N-acetyl galactosaminyl transferase 14 (GALNT14) and most down-regulated genes included C-X-C motif chemokine ligand 14 (CXCL14), urotensin 2 (UTS2D), and fibroblast growth factor 13 (FGF13). Pathways related with cell proliferation and angiogenesis, migration and invasion, cell death, cell cycle, signal transduction, and metabolism were highly enriched in cells that lack CD82 expression. Expression of two mutually inclusive genes in top 100 gene lists of all data sets, runt-related transcription factor (RUNX3) and trefoil factor 3 (TFF3), could be validated with qRT-PCR. Conclusion Identification of genes and pathways regulated by CD82 in this study may provide additional insights into the role that CD82 plays in prostate tumor progression and metastasis, as well as identify potential targets for therapeutic intervention.

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