UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that adenoviral vector-mediated interferon (IFN)-beta gene therapy inhibits orthotopic growth of human prostate cancer cells in nude mice. The purpose of this study was to determine efficacy and mechanisms of this therapy in immune-competent mice. TRAMP-C2Re3 mouse prostate cancer cells infected with 100 multiplicity of infection (MOI) of adenoviral vector encoding for mouse IFN-beta (AdmIFN-beta), but not AdE/1 (a control adenoviral vector), produced approximately 60 ng/10(5) cells/24 h of IFN-beta. The tumorigenicity of AdmIFN-beta-transduced cells was dramatically reduced in the prostates of C57BL/6 mice. A single intratumoral injection of 2 x 10(9) PFU (plaque-forming unit) of AdmIFN-beta inhibited tumor growth by 70% and prolonged survival of tumor-bearing mice. Intriguingly, this AdmIFN-beta therapy did not alter the growth of tumors in inducible nitric oxide synthase (iNOS)-null C57BL/6 mice. Immunohistochemical analysis revealed that treatment of tumors with AdmIFN-beta in wild-type C57BL/6 mice led to increased iNOS expression, decreased microvessel density, decreased cell proliferation, and increased apoptosis. Furthermore, quantitative reverse-transcriptional PCR analysis showed that AdmIFN-beta therapy, in C57BL/6 but not the iNOS-null counterparts, reduced levels of the mRNAs for angiopoietin, basic fibroblast growth factor, matrix metalloproteinase-9, transforming growth factor-beta1, vascular endothelial growth factor (VEGF)-A, and VEGF-B, as well as the antiapoptotic molecule endothelin-1. These data indicated that IFN-beta gene therapy could be effective alternative for the treatment of locally advanced prostate cancer and suggest an obligatory role of NO in IFN-beta antitumoral effects in vivo.
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PMID:Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-beta gene therapy. 1647 Feb 11

Prostate cancer is a leading cause of death from cancer in American men and metastasis the main cause of death. To better understand the disease and accelerate development of new therapies, in vivo models that reflect different disease stages are needed. A family of cell lines that mimics multiple steps in cancer development and tumor progression has been developed in our laboratory from the parent, non-tumorigenic, RWPE-1 cell line by transformation with N-methyl-N-nitrosourea (MNU). The MNU cell lines mimic multiple steps in tumor progression where WPE1-NB26 is the most malignant cell line. WPE1-NB26 cells form metastases in the lungs of athymic, male, nude mice after intravenous injection. Two new cell lines, WPE1-NB26-64 and WPE1-NB26-65, showing more malignant characteristics than the parent WPE1-NB26 cell line, were derived from tumors after subcutaneous injection of WPE1-NB26 cells into nude mice. The WPE1-NB26-64 and WPE1-NB26-65 cell lines show an increase in anchorage-dependent growth and invasive ability as compared to the parent WPE1-NB26 cells. While the parent WPE1-NB26 cells express barely detectable levels, the new cell lines produce high levels of matrix metalloproteinase MMP-2 and detectable levels of MMP-9. By immunostaining, all three cell lines were positive for cytokeratins CK18 and CK5/14. These cell lines, having the same lineage, represent additional steps in the multi-step process of tumor progression and provide novel and useful cell models for studies on tumor progression and for drug development for the treatment of prostate cancer.
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PMID:Selection of cell lines with enhanced invasive phenotype from xenografts of the human prostate cancer cell line WPE1-NB26. 1647 Oct 37

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

CD147, also named extracelluar matrix metalloproteinase inducer (EMMPRIN), has been proved to be involved in the invasion and metastasis processes of tumor cells in many types of cancers. To determine the role of CD147 in the invasiveness properties of prostate cancer, we successfully downregulated CD147 by RNA interference (RNAi) technology, in PC-3 cell line at high level of CD147 expression. PC-3 cells were transfected with a pSilencer 4.1-CMV neo Vector coding for an RNA composed of two identical 19-nucleotide sequence motifs in an inverted orientation, separated by a 9-bp spacer to form a hairpin dsRNA capable of mediating target CD147 inhibition. Gelatin zymography was employed to determine the effect on reducing secretions of MMP-2 and MMP-9 of the transfected cells. Matrigel invasion assay was performed to evaluate the invasion ability of PC-3 cells in vitro. Our results showed that CD147 expression was significantly inhibited by small interfering RNAs (siRNA) transfectants in PC-3 cells at mRNA and protein levels, which resulted in dramatic reduction of invasion ability in tumor cells. Moreover, downregulation of CD147 resulted in reducing secretions of MMP-2, MMP-9. Taken together, CD147 downregulation by RNAi technology decreases the invasive capability of prostate cancer cells, demonstrating that stable expression of siRNA CD147 could potentially be an experimental approach for prostate cancer gene therapy.
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PMID:Inhibition of CD147 expression reduces tumor cell invasion in human prostate cancer cell line via RNA interference. 1662 83

Camptothecin (CPT) was conjugated to the N-terminal of a somatostatin analog (SSA) directly via a carbamate group and a basic N-terminal linking motif, D-Lys-D-Tyr-Lys-D-Tyr-D-Lys. This new CPT-SSA conjugate termed JF-10-81 was evaluated as a receptor-specific delivery system for its anti-invasive and anti-angiogenic activities. It was found that, in addition to blocking migration and invasion of highly invasive prostate cancer PC-3 cells, this conjugate also inhibited in vitro capillary-like tube formation of endothelial cells and in vivo angiogenesis in C57B1/6N female mice. JF-10-81 was found to block PC-3 cell attachment to various extracellular matrix components, mainly to vitronectin, the ligand of cell surface receptors integrin alphaVbeta3 and alphaVbeta5. Additionally, JF-10-81 reduced expression of integrins alphaVbeta3 and alphaVbeta5 on PC-3 cell surfaces, without effects on beta1 or any alphabeta1 heterodimers. This conjugate also inactivated phosphorylation of protein kinase B (PKB/Akt), down-regulated the expression of latent matrix metalloproteinase (MMP) -2 and MMP-9, but had little effect on MMP-3/-10. Meanwhile, membrane type-1 matrix metalloproteinase (MT1-MMP) and the tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) were not detectable in PC-3 cells. alphaVbeta3/alphaVbeta5 and MMP-2/-9 are known to be highly expressed in many tumor cells and play an important role in tumor progression. Our results support that this conjugate could possibly inhibit prostate cancer PC-3 cell invasion through a signaling pathway involving PI3K/Akt, alphaVbeta3/alphaVbeta5 and MMP-2/-9, and this SSA could be used as an efficient vector to deliver CPT or other cytotoxic agents to target sites for cancer therapy.
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PMID:A conjugate of camptothecin and a somatostatin analog against prostate cancer cell invasion via a possible signaling pathway involving PI3K/Akt, alphaVbeta3/alphaVbeta5 and MMP-2/-9. 1664 5

Bone metastasis is very common in advanced prostate cancer. Docetaxel has been shown to improve survival in patients with metastatic prostate cancer. However, treatment with docetaxel is associated with a certain degree of toxicity. Genistein, derived from soybeans, has been found to inhibit cancer cell growth without toxicity. We have recently reported that genistein could potentiate the antitumor activity of chemotherapeutic agents both in vitro and in vivo. However, the molecular mechanism of this novel effect of genistein has not been fully elucidated. In this study, we found that genistein significantly potentiated the antitumor, anti-invasive, and antimetastatic activities of docetaxel both in culture and in severe combined immunodeficient (SCID)-human model of experimental prostate cancer bone metastasis. We further conducted microarray analysis, real-time reverse transcription-PCR, Western blot analysis, small interfering RNA and cDNA transfection, matrix metalloproteinase-9 (MMP-9) activity assay, and invasion assay. We found that the expression of osteoprotegerin (OPG) was induced by genistein and inhibited by docetaxel, whereas genistein significantly down-regulated the expression and secretion of receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL) and inhibited osteoclast formation. Moreover, genistein down-regulated the expression and activity of MMP-9, which was induced by docetaxel treatment, and inhibited invasion of PC-3 cells. These results suggest that the observed potentiation of antitumor activity of docetaxel by genistein in the SCID-human model of experimental bone metastasis could be mediated by regulation of OPG/RANK/RANKL/MMP-9 signaling, resulting in the inhibition of osteoclastic bone resorption and prostate cancer bone metastasis. From these results, we conclude that genistein could be a promising nontoxic agent to improve the treatment outcome of metastatic prostate cancer with docetaxel.
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PMID:Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/MMP-9 signaling in prostate cancer. 3021 85

Genistein is a candidate cancer chemopreventive drug being tested in clinical trials. We have shown that genistein blocks prostate cancer (PCa) cell invasion, that p38 mitogen-activated protein (MAP) kinase regulates activation of matrix metalloproteinase type 2 (MMP-2) and cell invasion, and that genistein prevents transforming growth factor beta (TGFbeta) from activating p38 MAP kinase. More recently, we identified MAP kinase-activated protein kinase 2 (MAPKAPK2) and the 27-kDa heat shock protein (HSP27) as downstream regulators of p38 MAP kinase. However, MAPKAPK2 and HSP27 can be regulated by factors other than p38 MAP kinase, and HSP27 is up-regulated during PCa progression. The current study was undertaken to examine the role of MAPKAPK2 and HSP27 in modulating genistein-mediated regulation of PCa cell invasion. Genistein inhibited TGFbeta-mediated phosphorylation of MAPKAPK2 and HSP27. Inhibitory effects by genistein upon cell signaling, inhibition of MMP-2, and inhibition of invasion were retained when both PC3 and PC3-M cells were transfected with either wild-type MAPKAPK2 or HSP27. However, transfection with dominant-negative MAPKAPK2 or nonphosphorylatable mutant HSP27 led to decreases in cell invasion and to abrogation of responsiveness to either TGFbeta-mediated increases or genistein-mediated decreases in MMP-2 and cell invasion. It is noteworthy that, after transfection with constitutive active MAPKAPK2 or with pseudophosphorylated HSP27, levels of MMP-2 activation and cell invasion were high and overcame any inhibitory effect of genistein. These findings demonstrate that genistein-mediated inhibition of cell invasion rests upon blocking activation of the MAPKAPK2-HSP27 pathway, and that its activation during cancer progression has the potential to mitigate therapeutic efficacy.
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PMID:Genistein inhibits matrix metalloproteinase type 2 activation and prostate cancer cell invasion by blocking the transforming growth factor beta-mediated activation of mitogen-activated protein kinase-activated protein kinase 2-27-kDa heat shock protein pathway. 1677 19

The regulation of tumor progression towards its malignancy needs the interplay among several cytokines, growth factors, and enzymes, which are controlled in the tumor microenvironment. Here, we report that osteopontin, a small integrin-binding ligand N-linked glycoprotein family of calcified extracellular matrix-associated protein, regulates prostate tumor growth by regulating the expression of cyclooxygenase-2 (COX-2). We have shown that osteopontin stimulates the activation of protein kinase C alpha/nuclear factor-inducing kinase/nuclear factor-kappaB-dependent signaling cascades that induces COX-2 expression, which in turn regulates the prostaglandin E(2) production, matrix metalloproteinase-2 activation, and tumor progression and angiogenesis. We have revealed that suppression of osteopontin-induced COX-2 expression by the nonsteroidal anti-inflammatory drug celecoxib or blocking the EP2 receptor by its blocking antibody resulted in significant inhibition of cell motility and tumor growth and angiogenesis. The data also showed that osteopontin-induced mice PC-3 xenograft exhibits higher tumor load, increased tumor cell infiltration, nuclear polymorphism, and neovascularization. Interestingly, use of celecoxib or anti-EP2 blocking antibody drastically suppressed osteopontin-induced tumor growth that further indicated that suppression of COX-2 or its metabolites could significantly inhibit osteopontin-induced tumor growth. Human clinical prostate cancer specimen analysis also supports our in vitro and animal model studies. Our findings suggest that blockage of osteopontin and/or COX-2 is a promising therapeutic approach for the inhibition of prostate tumor progression and angiogenesis.
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PMID:The crucial role of cyclooxygenase-2 in osteopontin-induced protein kinase C alpha/c-Src/IkappaB kinase alpha/beta-dependent prostate tumor progression and angiogenesis. 1681 37

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

We tested the hypothesis that cell invasiveness and tumorigenesis are driven by hypomethylation of genes involved in tumor progression. Highly invasive human prostate cancer cells PC-3 were treated with either the methyl donor S-adenosylmethionine (SAM) or methyl DNA-binding domain protein 2 antisense oligonucleotide (MBD2-AS). Both treatments resulted in a dose- and time-dependent inhibition of key genes, such as urokinase-type plasminogen activator (uPA), matrix metalloproteinase-2 (MMP-2), and vascular endothelial growth factor expression to decrease tumor cell invasion in vitro. No change in the levels of expression of genes already known to be methylated in late-stage prostate cancer cells, such as glutathione S-transferase P1 and androgen receptor, was seen. Inoculation of PC-3 cells pretreated with SAM and MBD2-AS into the flank of male BALB/c nu/nu mice resulted in the development of tumors of significantly smaller volume compared with animals inoculated with PC-3 cells treated with vehicle alone or MBD2 scrambled oligonucleotide. Immunohistochemical analysis of tumors showed the ability of SAM and MBD2-AS to significantly decrease tumoral uPA and MMP-2 expression along with levels of angiogenesis and survival pathway signaling molecules. Bisulfite sequencing analysis of tumoral genomic DNA showed that inhibition of both uPA and MMP-2 expression was due to methylation of their 5' regulatory region. These studies support the hypothesis that DNA hypomethylation controls the activation of multiple tumor-promoting genes and provide valuable insight into developing novel therapeutic strategies against this common disease, which target the demethylation machinery.
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PMID:Alteration of the methylation status of tumor-promoting genes decreases prostate cancer cell invasiveness and tumorigenesis in vitro and in vivo. 1698 64

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