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)

Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a highly restricted profile of expression. Expression is primarily limited to secretory cells of the prostatic epithelium, with elevated levels observed in prostate cancer. As an integral membrane protein correlated with prostate cancer, PSMA offers a potentially valuable target for immunotherapy. PSMA is also detected in the neovasculature of a variety of solid tumors but not in the endothelial cells of preexisting blood vessels. Although the significance of PSMA expression in these cells remains elusive, this pattern of expression implies that PSMA may perform a functional role in angiogenesis and may offer a therapeutic target for the treatment of a broad spectrum of solid tumors. In this study, we have expressed PSMA in human microvascular endothelial cells and demonstrate that PSMA binds to caveolin-1 and undergoes internalization via a caveolae-dependent mechanism. The association between PSMA and caveolae in endothelial cells may provide important insight into PSMA function and ways to best exploit this protein for therapeutic benefit.
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PMID:Association of prostate-specific membrane antigen with caveolin-1 and its caveolae-dependent internalization in microvascular endothelial cells: implications for targeting to tumor vasculature. 1671 5

Efforts to evaluate and discover diagnostic and therapeutic markers for prostate cancer continue. One of these, prostate-specific membrane antigen (PSMA), a transmembrane protein expressed in all types of prostatic tissue, remains a useful diagnostic and possibly therapeutic target. The radio-immunoconjugate form of the anti-PSMA monoclonal antibody 7E11 is used in the commercially available and US Food and Drug Administration-approved diagnostic tool, the ProstaScint(R) (Cytogen Corporation, Princeton, NJ) scan. Recent studies have demonstrated other possible useful roles for PSMA as a target, not only in prostate cancer, but in other malignancies.
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PMID:Overview of prostate-specific membrane antigen. 1698 27

IL-17RC (interleukin-17 receptor-like) gene codes for a transmembrane protein, the full length of which inhibits apoptosis in prostate cancer cells. IL-17RC gene transcribes over a dozen different splice variants of mRNA. However, it is not known whether there are relevant protein isoforms. Here we report that different IL-17RC protein isoforms were detected by two different antibodies. The isoform as detected byanti-IL-17RC intracellular domain antibodies (anti-ICD) was expressed at higher levels in androgen-independent prostate cancer cell lines (PC3 and DU145) than in androgen-dependent prostatic cell lines (RWPE-1, pRNS-1-1, MLC-SV40, and LNCaP). In contrast, several isoforms as detected by anti-IL-17RC extracellular domain antibodies (anti-ECD) were expressed at significantly higher levels in androgen-dependent prostatic cell lines than in androgen-independent ones. Furthermore, immunohistochemical staining of prostate tissue microarrays showed that IL-17RC protein expression was significantly higher in androgen-independent prostate cancers than in androgen-dependent ones when anti-ICD was used, whereas the trend was reversed using anti-ECD. These observations provide evidence that IL-17RC protein isoforms are differentially expressed in prostatic cells and cancer tissues and may play a negative or positive role in the initiation and progression of prostate cancer.
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PMID:Differential expression of IL-17RC isoforms in androgen-dependent and androgen-independent prostate cancers. 1760 28

The transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is expressed in prostate and brain and shed from the cell surface in a metalloproteinase-dependent fashion. Neither the sheddase(s) responsible for TMEFF2 shedding nor the physiological significance or activity of the soluble TMEFF2 ectodomain (TMEFF2-ECD) has been identified. In the present study we present new evidence that a disintegrin and metalloproteinase-17 (ADAM17) is responsible for phorbol 12-myristate 13-acetate-induced release of TMEFF2-ECD using small interfering RNA to ablate ADAM17 expression or by inhibiting enzymatic activity. A single well shedding assay monitoring the release of alkaline phosphatase-tagged TMEFF2-ECD into medium and the generation of 22- and 14-kDa C-terminal fragments in lysates were dependent on ADAM17 activity. A gamma-secretase inhibitor prevented the formation of a 10-kDa fragment in cell lysates, thus establishing TMEFF2 as a novel substrate for regulated intramembrane proteolysis. We assigned proliferation-inducing activity to TMEFF2. Inhibition of TMEFF2 shedding using synthetic metalloproteinase inhibitors or small interfering RNA targeting TMEFF2 expression yielded a statistically significant reduction of cell proliferation in the lymph node-derived prostate cancer cells (LNCaPs) and a human embryonic kidney (HEK293) cell line overexpressing TMEFF2. The TMEFF2-ECD was able to induce ERK1/2 phosphorylation in an epidermal growth factor receptor (or ErbB1)-dependent manner in HEK293 cells. Our data suggest that TMEFF2 contributes to cell proliferation in an ADAM17-dependent autocrine fashion in cells expressing this protein.
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PMID:Phorbol ester-induced shedding of the prostate cancer marker transmembrane protein with epidermal growth factor and two follistatin motifs 2 is mediated by the disintegrin and metalloproteinase-17. 1794 4

Prostate-specific membrane antigen (PSMA) is a transmembrane protein highly expressed in advanced and metastatic prostate cancers. The pathologic consequence of elevated PSMA expression in not known. Here, we report that PSMA is localized to a membrane compartment in the vicinity of mitotic spindle poles and associates with the anaphase-promoting complex (APC). PSMA-expressing cells prematurely degrade cyclin B and exit mitosis due to increased APC activity and incomplete inactivation of APC by the spindle assembly checkpoint. Further, expression of PSMA in a karyotypically stable cell line induces aneuploidy. Thus, these findings provide the first evidence that PSMA has a causal role in the induction of aneuploidy and might play an etiologic role in the progression of prostate cancer.
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PMID:Prostate-specific membrane antigen associates with anaphase-promoting complex and induces chromosomal instability. 1864 24

TMSG-1 was a tumor metastasis-related gene identified using mRNA differential display, whose expression level was lower in cancer cell lines with higher metastatic potential and in tumor tissue with metastasis. TMSG-1 was transfected to prostate cancer cell line (PC-3M-1E8) with high metastatic potential to observe the effects of increased expression of TMSG-1 on V-ATPase activity, intracellular pH and cell apoptosis. Subcellular localization of the encoded protein of TMSG-1 was determined by using GFP. Results showed that there were no differences of V-ATPase activity among parental PC-3M-1E8 cell line, pcDNA3 transfectant and anti-TMSG-1 transfectant, whereas the V-ATPase activity was significantly higher in TMSG-1 transfectant than that in parental PC-3M-1E8 cell line, pcDNA3 transfectant and Anti-TMSG-1 transfectant (p<0.001). Intracellular pH (pHi) was detected by using the pH-dependent fluorescence probe BECEF. Results showed the pHi was significantly increased in TMSG-1 transfectant. Cell apoptosis assay demonstrated cell apoptosis was significantly higher in -1 transfectant (p<0.01) and BCL2 expression was down regulated. Subcellular localization of TMSG-1 protein showed TMSG-1 was a transmembrane protein, which predicted TMSG-1 protein was located in cytoplasm system, such as endoplasmic reticulum and mitochondrial. These results indicated TMSG-1 up regulation in prostate cancer cell line could promote V-ATPase activity, increase pHi and cell apoptosis, and inhibit the expression of BCL2.
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PMID:Primary functional identification of gene TMSG-1. 1875 21

Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is overexpressed in advanced stage prostate adenocarcinomas. As a novel target for in vivo prognostic and therapeutic approaches, the distribution pattern of PSMA in primary and metastatic tumors is of significant interest. In this study we addressed the cellular distribution and heterogeneity of PSMA expression. Paraffin-embedded sections of 51 patients with primary prostate carcinoma and distant metastases were evaluated. Immunohistochemistry was used to determine the cellular localization, staining intensity and positive cell fraction which were related to tumor type and growth pattern. We demonstrated differences in the intracellular localization of the PSMA immunostaining which seem to be related to the tumor differentiation pattern. A significant number of the primary tumors (7/51) and metastases (6/51) presented with highly heterogeneous PSMA expression and in further 2 primary, and 8 metastatic tumors the staining was in the negative range (<10% positive tumor cells). A direct correlation between histological parameters and PSMA expression could not be demonstrated. Our findings clearly support the feasibility but also direct to potential failures of PSMA-targeted in vivo diagnostic and therapeutic approaches in prostate cancer patients with distant metastasis.
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PMID:Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis. 1880 90

Recent studies have shown a unique chromosomal rearrangement that leads to the fusion of 5'-transmembrane protein serine proteinase-2 (TMPRSS2) with the EST-related gene (ERG) in prostate cancer. In this study, we used fluorescence in situ hybridization to evaluate TMPRSS2-ERG gene fusion in prostate cancer of different zonal origins. Radical prostatectomy specimens with multifocal prostate cancer were obtained from 30 patients who were treated at our institution. Two separate tumor foci in each specimen, one in the peripheral zone and the other in the transition zone, were selected for gene fusion analysis. The selected peripheral zone tumor foci had a mean Gleason score of 6.8 (range, 6-7) and a mean tumor volume of 1.2 cm(3) (range, 0.1-4.6 cm(3)). The selected transition zone tumor foci had a mean Gleason score of 6.7 (range, 5-8) and a mean tumor volume of 4.0 cm(3) (range, 0.5-9.0 cm(3)). ERG gene rearrangement was not observed in any transition zone tumors; however, it was found in the peripheral zone tumors in 13 cases (43%). In 10 cases, the rearrangement was associated with the deletion of the 5'-end of ERG. In conclusion, we found that TMPRSS2-ERG gene fusion is associated with the zonal origin of prostate cancer. This gene fusion is prevalent in prostate cancer arising from the peripheral zone, but is lacking in prostate cancer arising from the transition zone.
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PMID:Prostate cancer of transition zone origin lacks TMPRSS2-ERG gene fusion. 2059 54

Prostate cancer continues to represent a major health problem, and yet there is no effective treatment available for advanced metastatic disease. Thus, there is an urgent need for the development of more effective treatment modalities that could improve the outcome. Because prostate specific membrane antigen (PSMA), a transmembrane protein, is expressed by virtually all prostate cancers, and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas, it is a very attractive target. Molecules targeting PSMA can be labelled with radionuclides to become both diagnostic and/or therapeutic agents. The use of PSMA binding agents, labelled with diagnostic and therapeutic radio-isotopes, opens up the potential for a new era of personalized management of metastatic prostate cancer.
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PMID:Prostate specific membrane antigen- a target for imaging and therapy with radionuclides. 2010 87

STAMP1 is predicted to encode a six-transmembrane protein whose expression is highly prostate enriched and is deregulated in prostate cancer. However, the biological role of STAMP1 in prostate cancer cells, or its expression profile at the protein level, is unknown. Here, we find that ectopic expression of STAMP1 significantly increased proliferation of DU145 prostate cancer cells as well as COS-7 cells in vitro; conversely, small interfering RNA-mediated knockdown of STAMP1 expression in LNCaP cells inhibited cell growth and, at least partially, induced cell cycle arrest. In parallel, there were alterations in cell cycle-regulatory gene expression. Knockdown of STAMP1 expression in LNCaP cells also induced significant apoptosis under basal conditions as well as in response to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) alone, or TRAIL + AKT inhibitor LY294002, previously established apoptotic agents in LNCaP cells. Consistently, LNCaP cells with short hairpin RNA-mediated knockdown of STAMP1 were dramatically retarded in their ability to grow as xenografts in nude mice. Interestingly, activation of extracellular signal-regulated kinase, which has previously been implicated in prostate cancer progression, was significantly increased on ectopic expression of STAMP1 in DU145 cells and, conversely, was strongly downregulated on STAMP1 knockdown in LNCaP cells. In the normal prostate, STAMP1 protein is localized to the cytosol and the cell membrane of the prostate epithelial cells; furthermore, its expression is increased in prostate cancer compared with normal prostate. Taken together, these data suggest that STAMP1 is required for prostate cancer growth, which may be a useful target in prostate cancer treatment.
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PMID:STAMP1 is both a proliferative and an antiapoptotic factor in prostate cancer. 2058 17


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