Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Considerable animal and human data have indicated that selenium is effective in reducing the incidence of several different types of cancer, including that of the prostate. However, the mechanism by which selenium inhibits carcinogenesis remains unknown. One possibility is that dietary selenium influences the levels of selenium-containing proteins, or selenoproteins. Selenoproteins contain selenium in the form of selenocysteine and perform a variety of cellular functions, including antioxidant defense. To determine whether the levels of selenoproteins can influence carcinogenesis independent of selenium intake, a unique mouse model was developed by breeding two transgenic animals: mice with reduced selenoprotein levels because of the expression of an altered selenocysteine-tRNA (i6A-) and mice that develop prostate cancer because of the targeted expression of the SV40 large T and small t oncogenes to that organ [C3(1)/Tag]. The resulting bigenic animals (i6A-/Tag) and control WT/Tag mice were assessed for the presence, degree, and progression of prostatic epithelial hyperplasia and nuclear atypia. The selenoprotein-deficient mice exhibited accelerated development of lesions associated with prostate cancer progression, implicating selenoproteins in cancer risk and development and raising the possibility that selenium prevents cancer by modulating the levels of these selenoproteins.
 ...
PMID:Selenoprotein deficiency accelerates prostate carcinogenesis in a transgenic model. 1669 Jul 48

The effects of leuprorelin acetate, a luteinizing hormone-releasing hormone agonist (LHRH-A), on prostate carcinogenesis in probasin/SV40 Tag transgenic rat was investigated. Fifteen weeks after administration of 0.28 and 2.8 mg/kg leuprorelin, prostate weights and serum testosterone levels were significantly decreased compared to values for transgenic controls. Histopathological findings revealed that the incidence of prostatic adenocarcinomas was significantly reduced in ventral, dorsal and lateral lobes of the prostate, correlating with decreased expression of SV40 Tag oncoprotein as well as inhibition of DNA synthesis and proliferation of epithelial cells in neoplastic lesions of the ventral prostate. Microarray analysis further showed leuprorelin acetate to significantly inhibit testicular steroidogenesis, suppressing the expression of SV40 Tag oncoprotein and altering the expression of a large number of genes which might be involved in the inhibition of prostate cancer progression in this rat model.
 ...
PMID:Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by leuprorelin, a luteinizing hormone-releasing hormone agonist. 1673 23

Rodents do not naturally develop prostate cancer. Currently, most widely used genetically engineered mouse prostate cancer models use SV40 T/tag oncogene. To understand the mechanism underlying prostate cancer development in transgenic and knock-in SV40 Tag mouse models, we did cDNA microarray analyses, comparing gene expression profiles of prostate cancer tissues from early-, late-, and advance-stage androgen-independent prostate cancers. Of the 67 genes that were up-regulated by > or = 10-fold, 40 are known to be required for chromosome stability. In particular, the spindle checkpoint component Bub1 was persistently up-regulated from early to advanced androgen-independent prostate cancer lesions. Significantly, Bub1, which is required for accurate chromosome segregation during mitosis, has recently been reported to bind SV40 Tag. Consistent with a spindle checkpoint defect, flow cytometry experiments indicate that advanced androgen-independent prostate cancer tumors exhibit aneuploidy, along with up-regulation of levels of both Bub1 mRNA and Bub1 protein or hyperphosphorylation. Importantly, up-regulation and hyperphosphorylation of Bub1 were also observed in established human prostate cancer cell lines and in clinical studies. Furthermore, analysis of human prostate cancer lines showed impaired spindle checkpoint function and endoreduplication following exposure to spindle toxins. Small interfering RNA-mediated repression of Bub1 in the human prostate cancer line PC-3 restrained cell proliferation, an effect mimicked by inhibition of mitogen-activated protein kinase, an upstream activator of Bub1. Thus, by perturbing Bub1 function, our observations suggest a new mechanism whereby the SV40 Tag oncoprotein promotes chromosomal instability and aneuploidy in transgenic mouse prostate cancer models. Whereas the exact details of this mechanism remain unclear, our novel findings raise the possibility of exploiting Bub1 as a new therapeutic target in the treatment of prostate cancer, the most common cancer in adult men in North America.
 ...
PMID:Bub1 up-regulation and hyperphosphorylation promote malignant transformation in SV40 tag-induced transgenic mouse models. 1718 86

High dietary calcium has been shown in epidemiological studies to be a risk factor for prostate cancer, and it has been postulated that this effect is secondary to calcium induced modulation of the vitamin D axis. In this study, we used LPB-Tag transgenic mice on the CD1 background to examine the impact of dietary calcium on prostate tumor progression. CD1-LPB-Tag mice predictably develop autochthonous, hormone-responsive prostate tumors by 3 months of age. Age matched transgenic and non-transgenic littermates were weaned onto high (2%) or low (0.2%) calcium diets and mice were sacrificed at 5, 7, and 9 weeks of age. The entire urogenital complex was excised, weighed, and processed for histology. There was no significant effect of dietary calcium on tumor weight or on the time course of tumor progression, as monitored using a modified Gleason grade (MGS). Serum calcium was maintained in the normal range in mice on the low and high calcium diet throughout the study. Circulating 1,25(OH)(2)D(3) was elevated by low dietary calcium in 5-week-old mice, but not in older animals. In summary, neither development nor progression of prostate tumors in LPB-Tag mice was accelerated by high dietary calcium.
 ...
PMID:Dietary calcium does not affect prostate tumor progression in LPB-Tag transgenic mice. 1730 54

Transgenic (TG) rats bearing a probasin promoter/simian virus 40 T antigen (SV40 Tag) construct were treated with antiandrogens to examine their ability to suppress prostate carcinogenesis. Finasteride and flutamide were administered to 10-week-old TG rats five times a week for 2, 5 and 7 weeks. Antiandrogen-treated prostates exhibited atrophic glandular structures with almost no expression of SV40 Tag and only weak signals for androgen receptors. Furthermore, quantitative data for ventral prostate adenocarcinomas showed significant decrease with antiandrogen treatment. Both finasteride and flutamide had the ability to suppress SV40 Tag-driven carcinogenesis through their different antiandrogenic mechanisms, suggesting that this TG model is suitable for exploring the potential of agents to inhibit prostate cancer development.
Prostate Cancer Prostatic Dis 2007
PMID:Suppressive effects of antiandrogens, finasteride and flutamide on development of prostatic lesions in a transgenic rat model. 1745 4

New therapeutic agents are needed for the treatment of androgen-independent prostate cancer (PrCa). We have investigated the effect of methylseleninic acid (MSA) on tumor stage-specific prostate cells derived from the C3 (1)/Tag model for PrCa: Pr111, a slow-growing and nontumorigenic cell line isolated from a prostate intraepithelial neoplasia lesion; Pr14, a tumorigenic line derived from a primary tumor; and Pr14C1, a sub-clone of Pr14 explanted from a lung metastasis. We demonstrate that MSA strongly inhibits cell growth and induces apoptosis in C3 (1)/Tag tumor cells, in a dose-dependent manner. A decrease in phosphorylated ERK1/2 and AKT was also found in tumor cells, but not in Pr111. Microarray analysis using affymetrix showed that the number of genes with an altered expression in tumor cells is significantly higher (p < 0.01) than in nontumoral cells. Pathways analyses revealed a decrease in the expression of genes involved in metabolism (Fabp5, Cyba), signal transduction (ERK, AKT), angiogenesis (neuropilin-1, Flt-4) and transcription (cAMP response element-binding protein) in tumor cells. The expression of neuropilin-1, a protein involved in VEGF signaling and tumor angiogenesis, was 97-fold repressed in Pr14 cells treated with MSA. Combination treatments using low doses of etoposide or taxotere (docetaxel), plus low doses of MSA revealed a strong enhancement of cell growth inhibition and apoptosis in tumor cells. Our in vivo studies using Pr14 cells xenografted into nude mice demonstrated that MSA significantly enhances the chemotherapeutical effect of etoposide, resulting in 78.3% tumor growth inhibition. These results suggest that MSA could be used against PrCa to enhance the effect of etoposide.
 ...
PMID:Methylseleninic acid enhances the effect of etoposide to inhibit prostate cancer growth in vivo. 1752 Jun 73

Mass spectrometry-based tissue profiling and imaging are technologies that allow identification and visualization of protein signals directly on thin sections cut from fresh frozen tissue specimens. These technologies were utilized to evaluate protein expression profiles in the normal mouse prostate during development (1-5 weeks of age), at sexual maturation (6 weeks of age), and in adult prostate (at 10, 15, or 40 weeks of age). The evolution of protein expression during normal prostate development and maturation were subsequently compared with 15-week prostate tumors derived from genetically engineered mice carrying the Large T antigen gene under regulation of the prostate-specific probasin promoter (LPB-Tag mouse model for prostate cancer). This approach identified proteins differentially expressed at specific time points during prostate development. Furthermore expression of some of these proteins, for example probasin and spermine-binding protein, were associated with prostate maturation, and prostate tumor formation resulted in their loss of expression. Cyclophilin A, a protein found in other cancers, was differentially alpha-acetylated on the N terminus, and both isoforms appeared during normal prostate and prostate tumor development. Imaging mass spectrometry localized the protein signals to specific prostatic lobes or regions. Thus, tissue profiling and imaging can be utilized to analyze the ontogeny of protein expression during prostate morphogenesis and tumorigenesis and identify proteins that could potentially serve as biomarkers for prostate cancer.
 ...
PMID:Monitoring mouse prostate development by profiling and imaging mass spectrometry. 1799 18

The transgenic adenocarcinoma of mouse prostate (TRAMP) model is widely used in prostate cancer research because of rapid tumor onset and progression. The transgenic mouse is on a C57BL/6 (B6) background and expresses SV40 T-antigen under the probasin promoter. The strong genetic component of susceptibility to prostate cancer in humans prompted us to investigate the effect of mouse strain background (FVB and B6) on incidence, progression, and pathology of prostate cancer in this model. Because TRAMP lesions are unique but differ from conventional prostatic intraepithelial neoplasia because the epithelium and stroma are affected diffusely, we designated them as "atypical hyperplasia of Tag." Although the incidence and severity of atypical hyperplasia of Tag is similar, FVB-TRAMP mice live significantly shorter lives than B6-TRAMP mice because of the rapid development and progression of neuroendocrine carcinomas. This is associated with an increased frequency of neuroendocrine precursor lesions in young TRAMP mice, detectable at 4 weeks after birth. These lesions show properties of bipotential stem cells and co-express markers of epithelial (E-cadherin) and neuroendocrine (synaptophysin) lineages, as well as the transcription factors Foxa1 and Foxa2. Transplantation studies using TRAMP prostatic ducts suggested that neuroendocrine carcinomas arise independently from atypical hyperplasias or other epithelial lesions. Adenocarcinomas were not seen in our cohort. Thus, neuroendocrine carcinomas are the principal malignancy in this model and may develop from bipotential progenitor cells at an early stage of prostate tumorigenesis.
 ...
PMID:Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. 1815 12

Expression of calcitonin (CT) and its receptor (CTR) is elevated in advanced prostate cancer (PC). Although the significance of CT-CTR axis in PC cell growth, invasion, and epithelial to mesenchymal transition has been established, its role in tumor metastasis has not been examined. To examine the role of CT-CTR axis in tumor metastasis, we employed stable CT-CTR activated and silenced system of three PC cell lines, LNCaP cells that lack endogenous CT, PC-3 cells that lack endogenous CTR, and PC-3M cells that co-express CT and CTR. Enforced expression of CT in LNCaP cells and CTR in PC-3 cells increased their ability to form orthotopic tumors and distant metastases in multiple organs. By contrast, silencing of CT expression in PC-3M cells not only reduced their tumorigenicity, but also completely abrogated their metastatic potential. To investigate the effect of in vivo silencing of CT expression on tumor growth, we employed recombinant adeno-associated virus (rAAV) to deliver anti-CT ribozymes in preexisting tumors of nude mice and large probasin promoter (LPB)-Tag transgenic mice. rAAV-CT(-) treatment not only abrogated the growth of pre-implanted tumors in nude mice, but also significantly reduced the growth of spontaneous tumors in LPB-Tag mice. Analysis of CT upregulated and silenced PC-3M transcriptomes revealed 105 genes affected by the modulation of CT expression. These CT signature genes generated survival, adhesion, pro-inflammatory, and pro-metastatic pathways. Added together, these data indicate a pivotal role for CT-CTR axis in PC metastasis and may serve as a potential therapeutic target for advanced PC.
 ...
PMID:Calcitonin promotes in vivo metastasis of prostate cancer cells by altering cell signaling, adhesion, and inflammatory pathways. 1878 82

Clinical trials have shown that chemotherapy with docetaxel (Doc) combined with prednisone can improve survival of patients with androgen-independent prostate cancer (AI-PC). It is likely that the combination of Doc with other novel agents would also improve the survival of AI-PC patients. We investigated whether the combination of Doc and 2-methoxyestradiol (2ME2), an endogenous metabolite of estradiol promising for cancer therapy, can increase apoptotic cell death in prostate cancer cells. Low concentration 2ME2 (0.5-1 microM)+Doc (0.05-0.1 nM) combinations inhibit cell growth, increase G2/M cell cycle arrest, and increase apoptosis more effectively than the single concentrations in a variety of human AI-PC cells. Effects on apoptosis were associated with an increase in p53 protein and a decrease in cyclin A-dependent kinase activity. We then investigated whether the combination of 2ME2+Doc can increase apoptotic cell death and inhibit the growth of prostate tumors in the FG/Tag transgenic mouse model of AI-PC. Doses of 2ME2 and Doc that increase mitotic cell cycle arrest result in an increase in apoptosis and lower primary prostate tumor weights in FG/Tag mice. High dose 2ME2+Doc combinations did not increase G2/M cell cycle arrest or apoptosis in AI-PC cell lines and in the FG/Tag mice more than the single drugs. Overall, our data indicate that low dose 2ME2+Doc combinations may provide a treatment strategy that can improve therapeutic efficacy against AI-PC while reducing toxicity often seen in patients treated with Doc.
 ...
PMID:Low dose combinations of 2-methoxyestradiol and docetaxel block prostate cancer cells in mitosis and increase apoptosis. 1904 2


<< Previous 1 2 3 4 Next >>