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

Prostate cancer (PCa) growth initially depends on circulating androgens. Gonadotropin-releasing hormone (GnRH) agonists are currently used for the treatment of PCa. However, after an initial responsiveness to hormonal deprivation, PCa progresses and metastasizes. Recently, also GnRH antagonists have been used for clinical trials in patients with PCa and the results seem promising. The components of the plasminogen activator (PA) system (urokinase-type PA, uPA; PA inhibitors, PAI-1/2; uPA receptor, uPAR) have been implicated in the local degradation of the extracellular matrix (ECM) and PCa progression. The aim of this study was to test the possible effects of the treatment with an agonist (Leuprolide, GnRH-A) and an antagonist (Cetrorelix, GnRH-ANT) of GnRH on the expression and activity of uPA and PAI-1 in the conditioned media of DU145 and PC3, two PCa androgen-independent cell lines. The involvement of the PA system in the control of cellular migration was also investigated. The results obtained in DU145 and PC3 cells show that both GnRH-A and GnRH-ANT: i) inhibit cell proliferation; ii) significantly decrease the enzymatic activity and the secretion of uPA; iii) significantly increase the protein levels of PAI-1; iv) induce a significant decrease of the migratory and invasion PCa capabilities. This study suggests that GnRH analogues exhibit not only an antiproliferative effect, but also an anti-metastatic action exerted through the inhibition of the activity of PA system and might provide a rational basis for the development of clinical strategies for those tumours that progress towards an androgen-independent condition characterized by a higher metastatic potential.
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PMID:GnRH agonists and antagonists decrease the metastatic progression of human prostate cancer cell lines by inhibiting the plasminogen activator system. 1639 60

The interaction between prostate cancer cells and bone marrow stromal cells (BMSC) is critical for survival and proliferation of metastatic cancer cells in the bone microenvironment. In order to study molecular mechanisms of prostate cancer bone metastasis, we established a novel heterotypic co-culture system, in which the role of direct cell-cell contact between prostate cancer cells and BMSC in addition to soluble factors can be analyzed. Using both bi-compartmental (insert) system and heterotypic (contact) system, we identified gene expression profiles of interaction between prostate cancer and bone cells. Analysis of differential gene expressions in these two co-culture systems revealed three distinctive sets of genes: 1) genes that were modified only by soluble factors; 2) genes that were regulated by both soluble factors and physical contact; and 3) genes that were altered only by physical contact. The last group consisted of specific set of genes including collagen III, IV, X, XII, integrin alpha1, alpha2, MMP-2, MMP-9, uPA, biglycan, osteopontin and raf-1 in PC3, and collagen VIII, IX, BMP6, TGFbeta1, Smad6 and Twist in BMSC. Among genes that were modified by both soluble factors and physical contact, the gene expression was affected in the same direction (such as MKK4) or in the opposite direction (such as TGFbeta receptor 3). Overall, this suggests that heterotypic cell-cell contact may act as an independent factor affecting the progression of bone metastasis.
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PMID:Identification of a unique set of genes altered during cell-cell contact in an in vitro model of prostate cancer bone metastasis. 1659 70

Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), has been implicated in bladder cancer angiogenesis and invasion. However, the molecular basis of its role in invasion remains unclear. We investigated the expression of TP and 10 invasion-related genes in bladder cancers from 72 randomly selected patients by real-time two-step RT-PCR assay. We found that the expression levels of TP, MMP-9, uPA, and MMP-2 were significantly higher in invasive tumors than those in superficial tumors. Also, the expression level of TP significantly correlated with that of uPA, MMP-1, MMP-9, PAI-1 and VEGF. KK47/TP cells, bladder cancer cells that overexpress TP, had a higher expression of MMP-7 and MMP-9 than KK/CV cells that express lower level of TP in hypoxic condition. PC/TP cells, prostate cancer cells that overexpress TP, also had a higher expression of MMP-1 and MMP-7 than PC/CV cells that express no detectable TP. Taken together these data indicate that TP enhances the invasion of tumor cells through the induction of invasion-related genes.
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PMID:Molecular basis for the involvement of thymidine phosphorylase in cancer invasion. 1668 20

Previously we reported that tyrosine kinase inhibitors (TKI) produced a reduction in uPA expression in prostatic cancer cells, and that TKI-treated cells were less invasive compared to untreated cells. Nevertheless, no change in cell migration was observed when TKI-treated cells were supplied with external uPA, thus indicating more complex mechanisms leading to decreased cell invasion. uPAR expression was measured with an enzyme-linked immunosorbent assay (ELISA) in PC-3 and DU-145 prostate carcinoma cells treated with the two TKI genistein and AG-1478. uPAR mRNA levels were measured with real-time reverse transcriptase-polymerase chain reaction (RT-PCR). uPAR immunocytochemistry was used to examine the receptor distribution in cells grown on a reconstituted basal lamina. Immunocytochemistry showed an intense uPAR immunostaining in invading cells, particularly in the leading edge membrane. Treatment with genistein and AG-1478 led to a decreased expression of uPAR in DU-145, but not in PC-3. Furthermore, a reduction of uPAR mRNA was found in TKI-treated DU-145 cells, while PC-3 was not affected. Our results indicate a possible role of TKI as cancer suppressors by acting as a regulator of uPAR expression.
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PMID:Urokinase plasminogen activator receptor (uPAR) expression is reduced by tyrosine kinase inhibitors. 1668 31

There is little understanding of the effect that reactive oxygen metabolites have on cellular behavior during the processes of invasion and metastasis. These oxygen metabolites could interact with a number of targets modulating their function such as enzymes involved in basement membrane dissolution, adhesion molecules involved in motility or receptors involved in proliferation. We investigated the effect of increased scavenging of superoxide anions on the expression of the urokinase receptor (uPAR) in PC-3M human prostate cancer cells. Urokinase receptor is a GPI-linked cell surface molecule which mediates multiple functions including adhesion, proliferation and pericellular proteolysis. Addition of the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy (TEMPOL) to PC-3M cultures stimulated expression of uPAR protein peaking between 48 and 72 hours. Cell surface expression of the uPAR was also increased. Surprisingly, uPAR transcript levels increased only slightly and this mild increase did not coincide with the striking degree of protein increase. This disparity indicates that the TEMPOL effect on uPAR occurs through a post-transcriptional mechanism. TEMPOL presence in PC-3M cultures reduced intracellular superoxide-type species by 75% as assayed by NBT dye conversion; however this reduction significantly diminished within hours following TEMPOL removal. The time gap between TEMPOL treatment and peak uPAR protein expression suggests that reduction of reactive oxygen metabolites in prostate cancer cells initiates a multistep pathway which requires several hours to culminate in uPAR induction. These findings reveal a novel pathway for uPAR regulation involving reactive oxygens such as superoxide anion.
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PMID:The superoxide scavenger TEMPOL induces urokinase receptor (uPAR) expression in human prostate cancer cells. 1675 81

The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.
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PMID:Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: a bench to bedside approach. 1678 42

Epidemiological studies have shown that the clinical incidence of prostate cancer varies by geographical area. When individuals move from low to high prostate cancer incidence areas, the risk of developing cancer increases to the level observed in the indigenous population. It was hypothesized that this observation is related to diet or more specifically to nutraceuticals present in food, medicinal plants, and herbs. Nutraceuticals can inhibit or downregulate enzymes critical for cancer formation. We tested this hypothesis by searching the 3D database of nutraceuticals and docking them to the 3D structure of urokinase. In addition to nutraceuticals, the data-base contains known uPA inhibitors that served as positive controls. From >1,000 compounds, several potential uPA inhibitors have been selected (antipain, leupeptin, folic acid, rosmarinic acid, lavendustin A, fisetin, myricetin, tolfenamic acid). Some of these were subject to further tests on inhibitory activity and inhibition of sprout formation. We found that compounds selected by computational methods indeed inhibit uPA and sprout formation. However, because the database of nutraceuticals was small, we did not expect to find either many or high affinity/specific inhibitors. Rather, we tested this method as a proof of concept. All the facts described above support the hypothesis that nutrients selected by computerized searches can inhibit unwanted uPA activity and thus reduce angiogenesis. If true, a proper diet rich in uPA-inhibiting nutraceuticals might support the prevention of prostrate cancer and be a supportive tool in prostate cancer treatment.
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PMID:Nutraceutical inhibitors of urokinase: potential applications in prostate cancer prevention and treatment. 1682 Sep 13

Matriptase is an epithelium-derived type II transmembrane serine protease and has been implicated in the activation of substrates such as pro-HGF/SF and pro-uPA, which are likely involved in tumor progression and metastasis. Through screening, we have identified bis-basic secondary amides of sulfonylated 3-amidinophenylalanine as matriptase inhibitors. X-ray analyses of analogues 8 and 31 in complex with matriptase revealed that these inhibitors occupy, in addition to part of the previously described S4-binding site, the cleft formed by the molecular surface and the unique 60 loop of matriptase. Therefore, optimization of the inhibitors included the incorporation of appropriate sulfonyl substituents that could improve binding of these inhibitors into both characteristic matriptase subsites. The most potent derivatives inhibit matriptase highly selective with K(i) values below 5 nM. Molecular modeling revealed that their improved affinity results from interaction with the S4 site of matriptase. Analogues 8 and 59 were studied in an orthotopic xenograft mouse model of prostate cancer. Compared to control, both inhibitors reduced tumor growth, as well as tumor dissemination.
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PMID:Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase. 1682 72

Hepsin, a type II transmembrane serine protease, is strongly up-regulated in prostate cancer. Hepsin overexpression in a mouse prostate cancer model resulted in tumor progression and metastasis, associated with basement membrane disorganization. We investigated whether hepsin enzymatic activity was linked to the basement membrane defects by examining its ability to initiate the plasminogen/plasmin proteolytic pathway. Because plasminogen is not processed by hepsin, we investigated the upstream activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator. Enzymatic assays with a recombinant soluble form of hepsin demonstrated that hepsin did not cleave pro-tissue-type plasminogen activator but efficiently converted pro-uPA into high molecular weight uPA by cleavage at the Lys158-Ile159 (P1-P1') peptide bond. uPA generated by hepsin displayed enzymatic activity toward small synthetic and macromolecular substrates indistinguishable from uPA produced by plasmin. The catalytic efficiency of pro-uPA activation by hepsin (kcat/Km 4.8 x 10(5) m(-1) s(-1)) was similar to that of plasmin, which is considered the most potent pro-uPA activator and was about 6-fold higher than that of matriptase. Conversion of pro-uPA was also demonstrated with cell surface-expressed full-length hepsin. A stable hepsinoverexpressing LnCaP cell line converted pro-uPA into high molecular weight uPA at a rate of 6.6 +/- 1.9 nm uPA h(-1), which was about 3-fold higher than LnCaP cells expressing lower hepsin levels on their surface. In conclusion, the ability of hepsin to efficiently activate pro-uPA suggests that it may initiate plasmin-mediated proteolytic pathways at the tumor/stroma interface that lead to basement membrane disruption and tumor progression.
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PMID:Pro-urokinase-type plasminogen activator is a substrate for hepsin. 1690 24

Despite advances in the understanding of prostate cancer (PCa) growth and development, it is still the leading incidence of cases and the second leading cause of mortality due to cancer in men. The problem of early diagnosis compounded with the emergence of androgen independence during commonly used anti-androgen therapy of PCa, have been discouraging for optimal therapeutic response. Recently, many chemopreventive agents, including silibinin, inositol hexaphosphate, decursin, apigenin, acacetin, grape seed extract, curcumin, and epigallocatechin-3 gallate have been identified in laboratory studies, which could be useful in the management of PCa. In vivo pre-clinical studies have indicated chemopreventive effect of many such agents in PCa xenograft and transgenic mouse models. The molecular targets of these agents include cell signaling, cell-cycle regulators, and survival/apoptotic molecules, which are implicated in uncontrolled PCa growth and progression. Furthermore, angiogenic and metastatic targets, including vascular endothelial growth factor, hypoxia-inducing factor-1alpha, matrix metalloproteinase, and urokinase-type plasminogen activator are also modulated by many chemopreventive agents to suppress the growth and invasive potential of PCa. This review focuses on novel PCa chemopreventive observations in laboratory studies, which could provide the rationale for the prospective use of chemopreventive agents in translational studies.
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PMID:Mechanisms of action of novel agents for prostate cancer chemoprevention. 1695 29


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