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)

Human prostate cancer displays a high degree of variability in its rate of spread, which could be due largely to differences in the invasive potential of the tumor cells. The degradation of the basal lamina and stromal extracellular matrix is mediated in part by the secretion of matrix metalloproteinases (MMPs). Matrilysin (PUMP-1, MMP-7) and gelatinase A (M(r) 72,000 type IV collagenase, MMP-2) have been shown to be overexpressed in prostate carcinoma. We have expressed the single MMP matrilysin in the tumorigenic but nonmetastatic human prostate tumor cell line DU-145 to determine if matrilysin has a functional role in prostate tumor cell invasion. DU-145 cells expressing matrilysin were significantly more invasive than vector-only transfected cell lines as assayed by a severe combined immunodeficient mouse model of tumor cell invasion. Vector-only transfected DU-145 cells injected i.p. into severe combined immunodeficient mice invaded the diaphragm in only 1 of 9 mice (11%), whereas matrilysin-transfected DU-145 cells invaded the diaphragm in 12 of 18 mice (66%). The difference between the controls and matrilysin-transfected cells was statistically significant (P < 0.006). These results suggest a functional role for matrilysin in the initial invasion of prostate cancer through the epithelial basal lamina and into the surrounding stroma.
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PMID:Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunodeficient mice. 841 33

Matrilysin (PUMP-1) is a member of the matrix metalloproteinase (MMP) family of extracellular matrix degrading enzymes that has been found to be overexpressed in human prostate cancer. The rat ventral prostate (RVP) following castration has been used as a model for both tissue involution and apoptosis. Northern analysis and in situ hybridization were used to determine the time course and localization of matrilysin during 8 days of RVP involution. Northern analysis revealed that the 1.2 kb matrilysin mRNA was undetectable in normal RVP. An increase in the steady-state levels of matrilysin mRNA was observed 5 days after castration, and the levels began to decline by 8 days after castration. The mRNAs for tissue inhibitor of metalloproteinase-1 and urokinase-type plasminogen activator also showed a time-dependent induction during the course of involution. Localization of matrilysin by in situ hybridization indicated that the mRNA was produced by epithelial cells of the involuting RVP. The matrilysin message was observed in a small number of glands within the whole RVP. Matrilysin protein was present in the RVP and peaked 3 days after castration. The combination of proteinase genes expressed in the RVP following castration indicate that the MMP and serine protease families of enzymes may interact during tissue remodeling of the RVP following castration.
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PMID:Matrilysin expression in the involuting rat ventral prostate. 882 84

Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins, and there is evidence that they play a role in tumor cell growth, invasion and metastasis. Matrilysin (MMP-7) is over-expressed in prostate cancer cells and increases prostate cancer cell invasion. Prostate stromal fibroblasts secrete a factor(s), including fibroblast growth factor-1 (FGF-1), which induces promatrilysin expression in the prostate carcinoma cell line LNCaP but not in normal prostate epithelial cells (PrECs). Since FGF-1 is present in the prostate, an altered sensitivity to FGF-1 might explain the up-regulation of matrilysin expression in prostate cancer cells compared to normal prostate epithelium. FGF receptor-1 (FGFR-1) is not normally expressed by normal prostate epithelial cells; however, aberrant expression of this receptor has been reported in prostate cancer cells, including the LNCaP cell line. We hypothesized that aberrant expression of FGFR-1 in PrECs would render them sensitive to induction of promatrilysin expression by recombinant FGF-1. To test this hypothesis, we transiently transfected PrECs with an FGFR-1 expression vector, which resulted in over-expression of FGFR-1 protein in approximately 40% of cells. FGF-1 increased promatrilysin expression in FGFR-1-transfected PrECs 4-fold over mock-transfected cells, and this induction was inhibited by a specific FGFR-1 inhibitor, SU5402, and by co-expression of a dominant negative FGFR-1 protein. Our results demonstrate that aberrant FGFR-1 expression, an epigenetic phenomenon that has been associated with prostate cancer progression, allows induction of promatrilysin expression by FGF-1 in PrECs.
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PMID:Aberrant expression of fibroblast growth factor receptor-1 in prostate epithelial cells allows induction of promatrilysin expression by fibroblast growth factors. 1114 43

Prostate cancer is the most frequently diagnosed malignancy in the Western world and changes in the ratio of testosterone and estrogens with advancing age is one of the potential risk factors in the development of this disease. However, the molecular mechanisms associated with hormone imbalance in prostate carcinogenesis are poorly understood. In this study we induced a high incidence of prostate hyperplasia, dysplasia and adenocarcinoma in the Noble rat using a combination of testosterone and estradiol-17beta. Using this animal model, we studied the gene expression profile during sex hormone-induced prostate carcinogenesis using a cDNA array technique; the results were further confirmed by RT-PCR, western blotting and immunohistochemical analyses. We found up-regulation of TRPM-2 (testosterone-repressed prostatic message-2), MMP-7 (matrix metalloproteinase-7) and Id-1 (inhibitor of differentiation or DNA binding) during development of sex hormone-induced prostate cancer. Increased expression of TRPM-2 and MMP-7 was observed in both premalignant and malignant tissues after sex hormone treatment, indicating their role in the early stages of hormone response and prostate cancer development. In contrast, Id-1 was expressed at relatively low levels in all premalignant samples but increased in malignant cells, suggesting its potential roles as a biomarker for prostate cancer cells. Furthermore, expression of Id-1 appeared to be stronger in poorly differentiated lesions than in well-differentiated carcinomas, suggesting that the levels of Id-1 expression may be correlated with the malignancy of tumors. Our results provide the first evidence of up-regulation of TRPM-2, MMP-7 and Id-1 during sex hormone-induced prostate carcinogenesis and strongly suggest their association with the development of prostate cancer.
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PMID:Up-regulation of TRPM-2, MMP-7 and ID-1 during sex hormone-induced prostate carcinogenesis in the Noble rat. 1137 6

The MMP, matrilysin (MMP-7), has been shown to be overexpressed in prostate cancer cells and to increase prostate cancer cell invasion. Prostate stromal fibroblasts secrete factor(s), including fibroblast growth factor-1 (FGF-1) that induces promatrilysin expression in LNCaP cells. In the present study, we investigated the signal transduction pathway involved in the FGF-1-induced expression of promatrilysin. FGF-1 treatment significantly increased the activation of extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2). This induction was time-dependent and was sustained until 24 hours after treatment. Treating the cells with MEK1/2 inhibitor (PD98059) eliminated ERK activation completely and blocked FGF-1-mediated induction of promatrilysin expression. Transient transfection studies with human matrilysin promoter resulted in a four- to five-fold increase in reporter luciferase enzyme activity that was blocked by the MEK1/2 inhibitor (PD98059). Serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) was observed after FGF-1 treatment and pretreatment with 20 microM PD98059-abolished STAT3 phosphorylation. Transient transfection with dominant negative STAT3 inhibited FGF-1-induced transactivation of the matrilysin promoter indicating that STAT3 plays an important role in FGF1-induced matrilysin expression. We propose that the FGF-1-induced signaling pathway that leads to promatrilysin expression is ERK-dependent and leads to phosphorylation of Ser-727 on STAT3, phosphorylated STAT3, then binds and transactivates the matrilysin promoter. Our results demonstrate that ERK-MAP kinase and transcription factor STAT3 are important components of FGF-1-mediated signaling, which induce promatrilysin expression in LNCaP cells.
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PMID:Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3. 1192 92

This work has explored a putative biochemical mechanism by which endometase/matrilysin-2/matrix metalloproteinase-26 (MMP-26) may promote human prostate cancer cell invasion. Here, we showed that the levels of MMP-26 protein in human prostate carcinomas from multiple patients were significantly higher than those in prostatitis, benign prostate hyperplasia, and normal prostate glandular tissues. The role of MMP-26 in prostate cancer progression is unknown. MMP-26 was capable of activating pro-MMP-9 by cleavage at the Ala(93)-Met(94) site of the prepro-enzyme. This activation proceeded in a time- and dose-dependent manner, facilitating the efficient cleavage of fibronectin by MMP-9. The activated MMP-9 products generated by MMP-26 appeared more stable than those cleaved by MMP-7 under the conditions tested. To investigate the contribution of MMP-26 to cancer cell invasion via the activation of MMP-9, highly invasive and metastatic human prostate carcinoma cells, androgen-repressed prostate cancer (ARCaP) cells were selected as a working model. ARCaP cells express both MMP-26 and MMP-9. Specific anti-MMP-26 and anti-MMP-9 functional blocking antibodies both reduced the invasiveness of ARCaP cells across fibronectin or type IV collagen. Furthermore, the introduction of MMP-26 antisense cDNA into ARCaP cells significantly reduced the MMP-26 protein level in these cells and strongly suppressed the invasiveness of ARCaP cells. Double immunofluorescence staining and confocal laser scanning microscopic images revealed that MMP-26 and MMP-9 were co-localized in parental and MMP-26 sense-transfected ARCaP cells. Moreover, MMP-26 and MMP-9 proteins were both expressed in the same human prostate carcinoma tissue samples examined. These results indicate that MMP-26 may be a physiological and pathological activator of pro-MMP-9.
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PMID:Activation of pro-gelatinase B by endometase/matrilysin-2 promotes invasion of human prostate cancer cells. 1258 37

We developed a rodent model that mimics the osteoblastic and osteolytic changes associated with human metastatic prostate cancer. Microarray analysis identified MMP-7, cathepsin-K, and apolipoprotein D as being upregulated at the tumor-bone interface. MMP-7, which was produced by osteoclasts at the tumor-bone interface, was capable of processing RANKL to a soluble form that promoted osteoclast activation. MMP-7-deficient mice demonstrated reduced prostate tumor-induced osteolysis and RANKL processing. This study suggests that inhibition of MMP-7 will have therapeutic benefit in the treatment of prostate cancer-induced osteolysis.
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PMID:MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. 1589 61

The role of matrix metalloproteinases (MMPs) as markers of tumor progression in prostate cancer (CaP) is complex and poorly understood. Using computerized image analysis, the differential expression of interstitial collagenase (MMP-1), gelatinase B (MMP-9), matrilysin-1 (MMP-7) and the membrane-type 1-MMP (MT1-MMP) in the epithelium and stroma of human prostate neoplastic tissues were investigated. Using immunohistochemistry and in situ hybridization techniques, 38 paraffin-embedded prostatic samples were analyzed and CaP was compared with prostate intraepithelial neoplasia (PIN) and its normal adjacent prostate (NAP) counterpart. The association of MMP protein and mRNA expression with Gleason histological tumor grade and TNM clinical stage was also determined. In most prostatectomy specimens examined, detectable amounts of MMP-1, MT1-MMP, MMP-7 and MMP-9 proteins and MT1-MMP and MMP-9 mRNA were found in the epithelial and stromal components of CaP, PIN and NAP. MMP expression was significantly stronger in the epithelium than in the stroma (p < 0.01). In the epithelium of normal and preneoplastic prostate tissue, MMP-1, MMP-9 and MT1-MMP were preferentially expressed in secretory luminal cells; conversely, MMP-7 was concentrated in basal cells. Epithelial and stromal expressions of MMPs differed in normal, preneoplastic and CaP tissues. Whereas MMP-1 was overexpressed in NAP epithelial glands and progressively decreased from PIN to CaP, MMP-7, MMP-9 and MT1-MMP were more strongly expressed in CaP than in PIN and NAP tissue. The MMPs investigated reached their highest levels in prostate tumors with high Gleason scores. The differential MMP expression in epithelial and stromal prostate tissue supports the previous hypothesis that MMPs may be autocrine and paracrine mediators of the stroma-epithelial interaction, an event that plays a critical role in regulating normal and abnormal prostate growth. MMP gene regulation changes during the early stage of prostate cancer. Differential expression of MMP components in CaP may reflect the malignant phenotype and more aggressive tumor behavior.
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PMID:Quantitative immunohistochemical and in situ hybridization analysis of metalloproteinases in prostate cancer. 1661 95

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

A series of new aminopteroyl-based hydroxamate derivatives were synthesized and tested in vitro in cell culture models as potential dual target drugs. These compounds were designed to target two families of enzymes, matrix metalloproteinases (MMP) and a folate enzyme, dihydrofolate reductase (DHFR). These enzymes are the components of two unrelated cellular pathways and they are often over-expressed in metastasizing tumors. In addition to the synthesis and full structural characterization of the hybrid molecules, we describe their inhibitory activities against a series of MMPs (MMP-2, MMP-7, MMP-9, MMP-14) and DHFR, as well as their antiproliferative activity in three cancer cell lines. The new hydroxamate derivatives of MTX proved to be effective inhibitors of MMPs and DHFR in the micromolar and nanomolar range, respectively. Furthermore, they showed strong antiproliferative activity against A549 cells (non-small cell lung carcinoma), and PPC-1 and Tsu-Pr1 prostate cancer cell lines. Therefore, based on the present results, these bi-functional drugs may be good candidates to target specific tumors in animal models due to potential combined effects on two pathways crucial for tumor development.
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PMID:Methotrexate gamma-hydroxamate derivatives as potential dual target antitumor drugs. 1712 67


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