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 tissue factor pathway inhibitor-2 (TFPI-2) is a 32-kDa serine protease inhibitor that inhibits plasmin, trypsin, chymotrypsin, cathepsin G, and plasma kallikrein but not urokinase and tissue-type plasminogen activators or thrombin. After discovering that TFPI-2 expression is down-regulated or lost during tumor progression, we investigated the role of TFPI-2 in the invasiveness of the prostate cancer cell line (LNCaP). We stably transfected LNCaP cells with a 0.7-kb vector expressing TFPI-2 in the sense orientation and measured the expression of TFPI-2 protein and mRNA by these cells by western and northern blotting. Neither TFPI-2 protein nor mRNA was expressed by parental LNCaP cells or vector-transfected controls, but levels of both protein and mRNA were significantly increased in the sense-TFPI-2 clones. The sense clones were less invasive than the control cells in Matrigel invasion and spheroid migration assays. This is the first demonstration that upregulation of TFPI-2 plays a significant role in the invasive behavior of human prostate cancer cells.
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PMID:Overexpression of tissue factor pathway inhibitor-2 (TFPI-2), decreases the invasiveness of prostate cancer cells in vitro. 1111 49

We used three human urological cancer cell lines, PC-3, LNCaP and SKRC-1, to investigate the effects of the extract from Serenoa repens (Palmae) on tumor cell invasion. The invasion activity of these cell lines was determined in vitro using a Transwell cell-culture chamber. The invasion activity of PC-3 cells into Matrigel was effectively suppressed by the extract at the concentration range of 1-10 microg/ml, while that of LNCaP and SKRC-1 cells was unaffected by the extract. The extract did not affect the viability, adhesion ability, or motility of the cell lines. uPA is more strongly expressed on the membrane fraction of PC-3 cells than that of LNCaP or SKRC-1 cells. The purified uPA activity is inhibited by the extract from S. repens in a dose-dependent manner, suggesting that the suppression of PC-3 cell invasion by the extract is based on an inhibition of the uPA activity which is necessary for tumor cell invasion. These data suggest that the extract from S. repens specifically inhibits the uPA activity and may therefore be useful for the therapeutic treatment of prostate cancer.
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PMID:Extract from Serenoa repens suppresses the invasion activity of human urological cancer cells by inhibiting urokinase-type plasminogen activator. 1121 90

Zinc is an essential heavy metal and is more abundant in human prostate and kidney than in other tissues. The effects of zinc on the invasion activity of human prostate and renal cancer cell lines, PC-3, LNCaP and SKRC-1, were investigated in vitro using a Transwell cell-culture chamber and were compared with specific protease inhibitors for MMPs, uPA and AP-N, respectively. The invasion activity of PC-3 cells was effectively suppressed by zinc and by all protease inhibitors in a dose-dependent manner. The invasion activity of LNCaP cells was almost unaffected by these inhibitors. In SKRC-1 cells, the invasion activity was strongly suppressed by MP03, although a moderate inhibition by zinc and bestatin was observed. The purified AP-N activity was strongly inhibited by zinc at a concentration similar to that suppressing the invasion activity of PC-3 cells and this inhibition by zinc was apparently competitive. Although the purified uPA activity was also inhibited by zinc, this inhibition was uncompetitive. AP-N was expressed abundantly on the membrane fraction of PC-3 cells among these cells tested, while its expression on the membrane fraction of SKRC-1 cells was weaker than that of PC-3 cells. The expression of uPA was also highest on the membrane fraction of PC-3 cells. These results suggest that AP-N and uPA may be involved in the invasion of human prostate cancer cells and that zinc probably participates in the invasion and metastasis of cancer cells through the regulation of the enzymatic activity of AP-N and uPA in human cancerous prostate.
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PMID:Inhibition of aminopeptidase N (AP-N) and urokinase-type plasminogen activator (uPA) by zinc suppresses the invasion activity in human urological cancer cells. 1125 75

The serine protease urokinase (uPa) has been implicated in the progression of both breast and prostate cancer. Utilizing structure based design, the synthesis of a series of substituted 4-[2-amino-1,3-thiazolyl]-thiophene-2-carboxamidines is described. Further optimization of this series by substitution of the terminal amine yielded urokinase inhibitors with excellent activities.
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PMID:Synthesis of thiophene-2-carboxamidines containing 2-aminothiazoles and their biological evaluation as urokinase inhibitors. 1129 90

To understand the fundamental determinants of urokinase plasminogen activator (uPA) driven angiogenesis in cancer we studied how inhibition of uPA activity could reduce neovascularization and consequently reduce tumor size in experimental animals. Proteolytic enzymes are required to mediate tumor cell invasion to adjacent tissues and initiate the metastatic process. Many different human cancers commonly overexpress the urokinase plasminogen activator system, one of the proteolytic enzyme systems. Reduction of urokinase activity in cancer cells is evidently associated with diminished invasion and metastasis. However, it has been shown recently that inhibitors of uPA could reduce tumor size also. The mechanism of action leading to decline in tumor growth rate is not clear. Proteolysis is responsible for degradation of proteins, for invasion or metastasis, but not for the proliferate properties of the cancer cells. It is difficult to envision that diminishing the size of tumor is due to simply blocking of uPA activity of cancer cells. Instead, inhibitors of uPA may be interacting with the elements of the extracellular matrix, such the neovascular bed surrounding tumors that has been reported to contain high amounts of uPA and its receptor. Overall these data strongly suggest that inhibitors of urokinase limit cancer growth by inhibiting angiogenesis. However, it is possible also that uPA inhibitors could act on cancer cells directly or prevent angiogenesis by alternative mechanisms that are not related to uPA inhibition. Therefore, we examined if plasminogen activator inhibitor (PAI-1) could limit angiogenesis. If it does, it will provide definitive evidence of uPA/PAI-1 involvement in reduction of cancer growth. Indeed, our study demonstrates that exogenously applied 14-1b PAI-1 is a powerful inhibitor of angiogenesis in three different in vitro models and is a powerful anti-cancer agent in a SCID mice model inoculated with human LNCaP prostate cancer cells.
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PMID:Recombinant PAI-1 inhibits angiogenesis and reduces size of LNCaP prostate cancer xenografts in SCID mice. 1129 64

Prostate cancer is the most common male malignancy in the United States as well as in many European countries. It is curable as long as it is localized, but the invasion of prostate cancer and formation of metastasis turn it into a life-threatening disease. Urokinase-type plasminogen activator (uPA) is believed to play a key role in tissue degradation and cell migration under various normal and pathological conditions, including cancer invasion and metastasis. Increased expression of uPA has been reported in various malignancies including prostate cancer. However, the mechanisms of the overexpression have remained poorly understood. Here, we report increased copy number of uPA gene in 3 of 13 hormone-refractory prostate carcinomas, including 1 high-level amplification. Real-time quantitative reverse transcription-PCR showed that the increased expression of uPA coincided with the amplification of the gene in these tumors. Matrigel invasion assay showed that prostate cancer cell line PC-3, containing amplification of the uPA gene, was more sensitive to the urokinase inhibitor, amiloride, than DU145 or LNCaP cell lines, which do not have the amplification. The findings suggest that one of the mechanisms underlying the overexpression of the uPA is the amplification of the gene, which is associated with the increased invasive potential of the cells.
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PMID:Amplification of urokinase gene in prostate cancer. 1145 71

There is a spectrum of presentations of skeletal manifestations of malignancy that includes generalized osteopenia and hypercalcemia, focal osteolysis, focal osteogenesis, and osteomalacia and hypophosphatemia. In various preclinical animal models, parathyroid hormone-related protein (PTHrP) was seen to be produced by tumor cells, causing osteolytic lesions, either with or without hypercalcemia. EB1089, an analog of 1,25-dihydroxyvitamin D3 [1,25 (OH)2D3], when used as a potential therapeutic agent, decreased both the number and size of metastatic bone lesions, the incidence of hind limb paralysis, and the volume of tumor burden within the bone, and also prolonged survival time. These findings were attributed to the interruption of pathways leading to PTHrP production. From studying osteoblastic metastases of prostate cancer in preclinical animal models, urokinase expression by the tumor was proposed as a growth factor and as an activator of other bone growth factors; however, the mechanism of action of osteoblastic metastases requires further research. The design of suitable preclinical animal models to study the pathophysiology of oncogenic osteomalacia also needs further investigation, though a genetic model of hypophosphatemic osteomalacia exists. The animal models and study designs used all establish methodologies that can be adapted for use in future clinical trials.
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PMID:Extending preclinical models of skeletal manifestations of malignancy to the clinical setting. 1154 70

Urokinase-type plasminogen activator (u-PA) contributes to tumor progression in prostate cancer (CaP). We have previously shown that u-PA expression is upregulated through the AP-1 and PEA3 sites and repressed by androgen. However, signaling pathways mediating u-PA gene expression in CaP are not delineated. We hypothesized that MAPK pathways mediate u-PA in CaP, and thereby studied specific ERK, JNK, and P38-MAPK pathway mutant constructs and inhibitors in vitro. Human, androgen insensitive CaP PC3 cells stably transfected with the androgen receptor expression vector and vector alone were used. A u-PA promoter CAT vector transiently expressed with dominant negative mutant signaling constructs was studied. All mutants drastically reduced u-PA promoter activity. Furthermore, inhibition of PI3K, an upstream regulator in the JNK/SAPK pathway, decreased u-PA promoter transcription. Collectively, these results show that MAPK pathways ERK, JNK/SAPK, and P38-MAPK represent a significant component in the regulation of u-PA expression in human CaP.
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PMID:Signal transduction-mediated regulation of urokinase gene expression in human prostate cancer. 1167 74

hK4 (prostase, KLK4), a recently cloned prostate-specific serine protease and a member of the tissue kallikrein family, is a zymogen composed of 228 amino acid residues including an amino-terminal propiece, Ser-Cys-Ser-Gln-. A chimeric form of hK4 (ch-hK4) was constructed in which the propiece of hK4 was replaced by that of prostate-specific antigen (PSA) to create an activation site susceptible to trypsin-type proteases. ch-hK4 was expressed in Escherichia coli, isolated from inclusion bodies, refolded, and purified with an overall yield of 25%. The zymogen was readily self-activated during the refolding process to generate an active form (21 kDa) of hK4 (rhK4). rhK4 cleaved the chromogenic substrates Val-Leu-Arg-pNA (S-2266), Pro-Phe-Arg-pNA (S-2302), Ile-Glu-Gly-Arg-pNA (S-2222), and Val-Leu-Lys-pNA (S-2251), indicating that rhK4 has a trypsin-type substrate specificity. The rhK4 was inhibited by aprotinin (6 kDa), forming an equimolar 27 kDa complex. rhK4 readily activated both the precursor of PSA (pro-PSA) and single chain urokinase-type plasminogen activator (scuPA, pro-uPA). rhK4 also completely degraded prostatic acid phosphatase but failed to cleave serum albumin, another protein purified from human seminal plasma. These results indicate that hK4 may have a role in the physiologic processing of seminal plasma proteins such as pro-PSA, as well as in the pathogenesis of prostate cancer through its activation of pro-uPA.
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PMID:Characterization of hK4 (prostase), a prostate-specific serine protease: activation of the precursor of prostate specific antigen (pro-PSA) and single-chain urokinase-type plasminogen activator and degradation of prostatic acid phosphatase. 1173 17

We review the extensive body of data on the molecular aetiology of hormone refractory disease in metastatic prostate cancer patients. Particular emphasis is placed on the crucial role of the bone micro-environment, especially the intercellular interactions of metastatic prostate cancer cells and osteoblasts in promoting the establishment of hormone refractory disease. Resistance of tumour cells to anticancer therapies is generally viewed as a phenomenon almost exclusively determined by chromosomal defects and/or gene mutations. However, it is now well-documented that the local milieu of the bone metastases can also protect tumour cells from anticancer therapy- induced apoptosis, either independently or synergistically with resistance-related genetic alterations. A key determinant of this protection is the urokinase/plasmin cascade which modulates the local concentration of survival factors, such as insulin-like growth factor (IGF-1). The molecular pathways whereby this major growth and survival factor for prostate cancer cells exerts its anti-apoptotic effect on prostate cancer cells are discussed.
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PMID:Molecular biology and cellular physiology of refractoriness to androgen ablation therapy in advanced prostate cancer. 1177 38


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