Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Therion Biologics is developing PROSTVAC, an immunotherapeutic vaccine that targets prostate-specific antigen, for the potential treatment of prostate cancer. In February 2000, phase II trials had commenced. By October 2001, the drug was undergoing four phase II trials.
Curr Opin Mol Ther 2002 Oct
PMID:Technology evaluation: PROSTVAC, Therion. 1243 56

Human prostate-specific antigen (PSA) is clinically most useful diagnostic marker for prostate cancer. The PSA gene is partially regulated by androgen hormone via androgen receptor (AR). Several transcription factors including novel transcriptional regulator, age-dependent factor (ADF) bind to AR promoter and play role in the regulation of AR gene expression. Earlier, an androgen responsive enhancer (-5824 to -3738) has been identified in 5'-flanking region of PSA gene. Here, we demonstrate by competitive electrophoretic mobility shift assay that ADF binds to a 19 bp sequence in PSA gene (-4372 to -4390) located within this enhancer region. This suggests that ADF may play a role in the regulation of PSA gene expression.
Mol Biol Rep 2002 Sep
PMID:Age-dependent transcription factor (ADF) interacts with prostate-specific antigen (PSA) gene enhancer. 1246 25

Research investigating the molecular events underlying progression of prostate cancer to androgen independence has been impeded by the lack of an appropriate in vivo model that yields "pure" populations of prostate cancer cells that are not contaminated with host cells. Here we characterize a new in vivo model that uses hollow fibers and allows for the retrieval of uncontaminated prostate cancer cells during various stages of endocrine progression to androgen independence in male immunocompromised mice. Prostate-specific antigen (PSA) gene expression, proliferation of cells, and histology were examined in these mice before and after castration. LNCaP cells seeded at a density of 1 x 10(7) cells/ml, or a total of approximately 4.8 x 10(6) cells/animal, provided measurable serum PSA levels that increased in intact (noncastrated) animals, decreased by 80% to a nadir after castration, and subsequently increased by 4 weeks after castration, indicating progression to androgen independence. In vivo proliferation of LNCaP cells inside the fibers continued in the presence of androgens and continued to increase, albeit at a slower rate, in the castrated animals. Histology of cells cultivated in hollow fibers demonstrated that initially the cells grew along the wall of the fiber and tended to stack up, forming layers and scaffold structures resembling a solid tumor. Fibers removed from castrated animals with elevated levels of serum PSA contained spheroids of cells that had detached from the fiber wall. The development of the LNCaP hollow fiber model described here provides a reproducible means of obtaining "pure" populations of LNCaP cells during different stages of progression to androgen independence for molecular analysis requiring RNA and protein extracts free of host cell contamination.
Mol Cancer Ther 2002 Jun
PMID:Characterization of a new in vivo hollow fiber model for the study of progression of prostate cancer to androgen independence. 1247 23

Currently, there is no therapy for men with androgen-refractory prostate cancer that substantially extends survival. This report characterizes by in vitro and in vivo techniques a new chemotherapeutic that is composed of desacetyl-vinblastine covalently linked to a peptide that contains a peptide bond that can be hydrolyzed by prostate-specific antigen (PSA). This compound (referred to as vinblastine-conjugate) is minimally toxic to cells in culture which do not express PSA. In the presence of PSA, the peptide moiety is hydrolyzed, generating several highly toxic metabolites that contain vinblastine. Animals bearing PSA-positive human prostate tumors that were treated with the vinblastine-conjugate experienced a >99% reduction in PSA serum level. In contrast, animals bearing PSA-positive human prostate tumors treated with the cytotoxic metabolites derived from the PSA hydrolysis of the vinblastine-conjugate showed a nonsignificant change in both PSA and tumor weight values. The cell killing activity of the vinblastine-conjugate is PSA dependent because animals bearing non-PSA-producing human tumor xenografts had a nonsignificant increase in tumor weight after vinblastine-conjugate treatment. Exploratory efficacy/toxicity studies in LNCaP tumor-bearing nude mice were conducted with animals treated for 5 consecutive days with various doses of either the vinblastine-conjugate or a PSA-generated toxic metabolite (desacetyl-vinblastine). The desacetyl-vinblastine treatment resulted in 10-70% mortality with a very slight effect on tumor growth. In contrast, vinblastine-conjugate treatments resulted in no mortality, good to excellent antitumor efficacy, very slight to slight peripheral neuropathy and myelopathy, and slight to severe testicular degeneration. Similar treatment of beagle dogs with the vinblastine-conjugate showed even less toxicity. These data support the use of the PSA-hydrolyzable vinblastine-conjugate as an experimental therapy for prostate cancer in man.
Mol Cancer Ther 2002 May
PMID:A prostate-specific antigen (PSA)-activated vinblastine prodrug selectively kills PSA-secreting cells in vivo. 1247 63

Treatment for prostatic adenocarcinoma is reliant on the initial androgen dependence of this tumor type. The goal of therapy is to eliminate androgen receptor activity, either through direct inhibition of the receptor or through inhibition of androgen synthesis. Although this course of therapy is initially effective, androgen-refractory tumors ultimately arise and lead to patient morbidity. Factors contributing to the transition from a state of androgen dependence to the androgen-refractory state are poorly understood, but clinical evidence in androgen-refractory tumors suggests that the androgen receptor is inappropriately activated in these cells. Thus, the mechanisms that contribute to inappropriate (androgen-independent) activation of the androgen receptor (AR) is an area of intensive research. Here we demonstrate that bisphenol A (BPA), a polycarbonate plastic monomer and established xenoestrogen, initiates androgen-independent proliferation in human prostatic adenocarcinoma (LNCaP) cells. The mitogenic capacity of BPA occurred in the nanomolar range, indicating that little BPA is required to stimulate proliferation. We show that BPA stimulated nuclear translocation of the tumor-derived receptor (AR-T877A), albeit with delayed kinetics compared with dihydrotestosterone. This translocation event was followed by specific DNA binding at androgen response elements, as shown by electrophoretic mobility shift assays. Moreover, the ability of BPA to stimulate AR-T877A activity was demonstrated by reporter assays and by analysis of an endogenous AR target gene, prostate-specific antigen. Thus, BPA is able to activate AR-T877A in the absence of androgens. Lastly, full mitogenic function of BPA is dependent on activation of the tumor-derived AR-T877A. These data implicate BPA as an inappropriate mitogen for prostatic adenocarcinoma cells and provide the impetus to study the consequence of BPA exposure on prostate cancer.
Mol Cancer Ther 2002 May
PMID:The xenoestrogen bisphenol A induces inappropriate androgen receptor activation and mitogenesis in prostatic adenocarcinoma cells. 1247 69

Blood serum is a complex body fluid that contains various proteins ranging in concentration over at least 9 orders of magnitude. Using a combination of mass spectrometry technologies with improvements in sample preparation, we have performed a proteomic analysis with submilliliter quantities of serum and increased the measurable concentration range for proteins in blood serum beyond previous reports. We have detected 490 proteins in serum by on-line reversed-phase microcapillary liquid chromatography coupled with ion trap mass spectrometry. To perform this analysis, immunoglobulins were removed from serum using protein A/G, and the remaining proteins were digested with trypsin. Resulting peptides were separated by strong cation exchange chromatography into distinct fractions prior to analysis. This separation resulted in a 3-5-fold increase in the number of proteins detected in an individual serum sample. With this increase in the number of proteins identified we have detected some lower abundance serum proteins (ng/ml range) including human growth hormone, interleukin-12, and prostate-specific antigen. We also used SEQUEST to compare different protein databases with and without filtering. This comparison is plotted to allow for a quick visual assessment of different databases as a subjective measure of analytical quality. With this study, we have performed the most extensive analysis of serum proteins to date and laid the foundation for future refinements in the identification of novel protein biomarkers of disease.
Mol Cell Proteomics 2002 Dec
PMID:Toward a human blood serum proteome: analysis by multidimensional separation coupled with mass spectrometry. 1254 31

The human prostate cancer cell line LNCaP bears functional membrane testosterone receptors, which modify the actin cytoskeleton and increase the secretion of prostate-specific antigen (PSA) within minutes. Membrane steroid receptors are, indeed, a newly identified element of steroid action that is different from the classical intracellular sites. In the present work, using a nonpermeable analog of testosterone (testosterone-BSA), we investigated the signaling pathway that is triggered by the membrane testosterone receptors' activation and leads to actin cytoskeleton reorganization. We report that exposure of cells to testosterone-BSA resulted in phosphorylation of focal adhesion kinase (FAK), the association of FAK with the phosphatidylinositol-3 (PI-3) kinase, and the subsequent activation of the latter as well as the activation of the small guanosine triphosphatases Cdc42/Rac1. Pretreatment of cells with the specific PI-3 kinase inhibitor wortmannin abolished both the activation of the small guanosine triphosphatases and the alterations of actin cytoskeleton, whereas it did not affect the phosphorylation of FAK. These findings indicate that PI-3 kinase is activated downstream of FAK and upstream of Cdc42/Rac1, which subsequently regulate the actin organization. Moreover, wortmannin diminished the secretion of PSA, implying that the signaling events described above are responsible for the testosterone-BSA-induced PSA secretion. Our results are discussed under the prism of a possible implication of these membrane receptors in prostate cancer chemotherapy.
Mol Endocrinol 2003 May
PMID:A rapid, nongenomic, signaling pathway regulates the actin reorganization induced by activation of membrane testosterone receptors. 1255 77

The data considered in the paper indicate that a tumor clone resulting from cell transformation, in order to develop, should overcome a microenvironmental constraint. This destroys intercellular contacts and cell interactions with extracellular matrix required for induction and maintenance of epithelium differentiation. The possible reasons for this lie in mutations of genes that control cell adhesion molecules and integrins, as well as proteases secreted by a tumor. These events lead to partial loss of differentiation antigens by a cell or to their incorrect localization in a cell. Simultaneously, the expression of embryo-specific genes is unblocked, leading to overexpression of embryonic antigens and their abnormal secretion into blood, which results in appearance of oncofetal markers in blood. Discussed from this point of view are alpha-fetoprotein, the carcinoembryonic antigen, and the prostate-specific antigen, which are used as tumor markers.
Mol Biol (Mosk)
PMID:[Differentiation antigens in tumors: dependence on carcinogenesis mechanisms and progression (a hypothesis)]. 1262 42

Androgen ablation has been the standard treatment for metastasized prostate cancer. In most cases, however, prostate cancer cells eventually lose androgen dependency and become refractory to the conventional endocrine therapy. Androgen-independent prostate cancer is characterized by a heterogeneous loss of androgen receptor (AR) expression among tumor cells. Prostate-specific promoters such as prostate-specific antigen and rat probasin (rPB) promoters have been examined in the development of gene therapy targeted to prostate cancer. However, those promoters require binding of the androgen-AR complex to the androgen-response element and are active only in the androgen-dependent prostate cancer cell lines and not in the androgen-independent cell lines. To target transgene expression in androgen-independent prostate cancer, we designed a prostate-specific promoter that is activated by the retinoids-retinoid receptor complex instead of the androgen-AR complex. The modified rPB promoters expressed transgenes in response to retinoid in both androgen-dependent and androgen-independent prostate cancer cells and not in other cancer cell lines or in human normal cells, in vitro and in vivo. Furthermore, the combination of retinoid treatment and adenovirus-mediated gene transfer of the modified rPB-driven HSV-tk gene resulted in a significant growth suppression of the androgen-independent prostate cancer cells in the presence of the prodrug ganciclovir. This study suggests that tailoring of the hormone-responsive elements may offer a new therapeutic opportunity against the hormone-refractory stage of prostate cancer.
Mol Ther 2003 Mar
PMID:Development of a prostate-specific promoter for gene therapy against androgen-independent prostate cancer. 1266 32

Androgens and mesenchymal factors are essential extracellular signals for the development as well as the functional activity of the prostate epithelium. Little is known of the intraepithelial determinants that are involved in prostatic differentiation. Here we found that hepatocyte nuclear factor-3 alpha (HNF-3 alpha), an endoderm developmental factor, is essential for androgen receptor (AR)-mediated prostatic gene activation. Two HNF-3 cis-regulatory elements were identified in the rat probasin (PB) gene promoter, each immediately adjacent to an androgen response element. Remarkably, similar organization of HNF-3 and AR binding sites was observed in the prostate-specific antigen (PSA) gene core enhancer, suggesting a common functional mechanism. Mutations that disrupt these HNF-3 motifs significantly abolished the maximal androgen induction of PB and PSA activities. Overexpressing a mutant HNF-3 alpha deleted in the C-terminal region inhibited the androgen-induced promoter activity in LNCaP cells where endogenous HNF-3 alpha is expressed. Chromatin immunoprecipitation revealed in vivo that the occupancy of HNF-3 alpha on PSA enhancer can occur in an androgen-depleted condition, and before the recruitment of ligand-bound AR. A physical interaction of HNF-3 alpha and AR was detected through immunoprecipitation and confirmed by glutathione-S-transferase pull-down. This interaction is directly mediated through the DNA-binding domain/hinge region of AR and the forkhead domain of HNF-3 alpha. In addition, strong HNF-3 alpha expression, but not HNF-3 beta or HNF-3 gamma, is detected in both human and mouse prostatic epithelial cells where markers (PSA and PB) of differentiation are expressed. Taken together, these data support a model in which regulatory cues from the cell lineage and the extracellular environment coordinately establish the prostatic differentiated response.
Mol Endocrinol 2003 Aug
PMID:The role of hepatocyte nuclear factor-3 alpha (Forkhead Box A1) and androgen receptor in transcriptional regulation of prostatic genes. 1275 Apr 53


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