Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Maspin, a novel serine protease inhibitor, suppresses tumor progression in several cancer models, including an in vivo model for prostate cancer bone metastasis. However, the molecular mechanism of maspin remains illusive, primarily because its molecular targets are unknown. To this end, we used a full-length maspin cDNA bait to screen against both a primary prostate tumor cDNA prey library and a HeLa cDNA prey library by the yeast two-hybrid method. We found that heat shock protein 90, glutathione S-transferase (GST), and heat shock protein 70 interacted with maspin with the highest frequencies. We confirmed the maspin/GST interaction using purified proteins, human epithelial cell lines, and human prostate tissues. A maspin variant that has a point mutation of Arg(340) to Ala (Mas(R340A)) showed a significantly decreased affinity for GST. Although purified maspin had no effect on the activity of purified GST in vitro, intracellular interaction between endogenous maspin and GST correlated with an elevated total GST activity in both MDA-MB-435- and DU145-derived stably transfected cells. Consistently, tumor cells treated with purified wild type maspin, but not Mas(R340A), enhanced cellular GST activity. Maspin expression in cancer cell lines also correlated with decreased basal levels of reactive oxygen species (ROS). Furthermore, H(2)O(2) treatment not only induced GST expression but also increased intracellular maspin/GST interaction, which was inversely correlated with the level of ROS generation. Conversely, maspin knockdown by small interfering RNA increased the basal, as well as H(2)O(2)-induced, ROS generation. Furthermore, the maspin effect on ROS generation was completely abolished by a GST inhibitor, indicating an essential role of GST in maspin-mediated cellular response to oxidative stress. Consistently, oxidative stress-induced vascular endothelial growth factor A expression was significantly inhibited in maspin-expressing cells. Together, our data suggest a new mechanism by which maspin, through its direct interaction with GST, may inhibit oxidative stress-induced ROS generation and vascular endothelial growth factor A induction, thus preventing further adverse effects on tumor genetics and stromal reactivity.
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PMID:Tumor-suppressive maspin regulates cell response to oxidative stress by direct interaction with glutathione S-transferase. 1604 7

The ability of an adenoviral vector expressing the melanoma differentiation-associated gene-7 (Ad-mda7) to mediate inhibition of vascular endothelial growth factor (VEGF) has recently been reported. However, the molecular mechanism by which Ad-mda7 inhibits VEGF is unknown. In an attempt to elucidate this mechanism, we studied the effects of Ad-mda7 on VEGF expression using human prostate cancer cells as a model. We found that Ad-mda7 treatment of prostate cancer cells (LNCaP and DU145) in vitro resulted in a significant (P < 0.05) inhibition of VEGF expression. Analysis of the VEGF signaling pathway showed that Ad-mda7 inhibited c-Src kinase activity and abrogated STAT-3 binding to the VEGF promoter. Correlating with these observations were reductions in VEGF mRNA and protein levels in Ad-mda7-treated cells. Furthermore, Ad-mda7 inhibited VEGF in Src(+/+) but not in Src(-/-) mouse embryo fibroblasts. These results showed that Ad-mda7 inhibited VEGF by inhibiting the Src signaling pathway. Finally, conditioned medium from Ad-mda7-treated tumor cells containing reduced VEGF inhibited VEGF receptor signaling, resulting in reduced endothelial cell proliferation and apoptosis. Our results provide evidence for the mechanism by which Ad-mda7 inhibits VEGF in tumor cells and of the effects of this VEGF inhibition on endothelial cell proliferation, a requirement for angiogenesis. Our findings demonstrate that MDA-7 protein, in addition to inhibiting tumor angiogenesis directly, inhibits angiogenesis indirectly by inhibiting VEGF production by tumor cells.
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PMID:Inhibition of Src kinase activity by Ad-mda7 suppresses vascular endothelial growth factor expression in prostate carcinoma cells. 1605 37

Geldanamycin (GA), a benzoquinone ansamycin, is a naturally occurring inhibitor of heat shock protein (Hsp90), which regulates the transcription activity of hypoxia-inducible factor 1 (HIF-1alpha). Under hypoxia, HIF-1alpha is activated in tumor cells, and induces the transcription of vascular endothelial growth factor (VEGF), which is the prime regulator for angiogenesis. VEGF promotes the formation of new blood vessels by stimulating endothelial cell division and migration. This eventually forms a vascular network that allows for tumor growth and metastasis. In this study, we used GA to inhibit HIF-1alpha transcription function. Human prostate cancer DU-145 cells were incubated in a hypoxic chamber at 1% O(2) and 37 degrees C for different durations. Both mRNA and protein levels of HIF-1alpha and VEGF were upregulated under hypoxic conditions. We demonstrated that GA treatment of hypoxic DU-145 cells abolished the induction of HIF-1alpha protein in a time-dependent manner and decreased VEGF mRNA and its protein levels. The transient transfection of DU-145 cells with luciferase reporter gene construct (5HRE/hCMVmp-luc) showed that the transcriptional activity of HIF-1alpha was significantly induced in response to hypoxia, but inhibited by GA. In addition, using conditioned medium from GA-treated hypoxic cells led to a significant decrease in cell invasion in comparison with using conditioned medium from nontreated hypoxic cells. These data provide evidence for the important role of GA in inhibition of angiogenesis and also invasion mediated by HIF-1alpha in prostate cancer cells.
Prostate Cancer Prostatic Dis 2006
PMID:Effects of geldanamycin on HIF-1alpha mediated angiogenesis and invasion in prostate cancer cells. 1643 34

The Wilms' tumor suppressor gene product (WT1) regulates expression of growth control genes. Microarray analysis of gene expression profiles of hormone-treated LNCaP prostate cancer cell lines transfected with either wild-type WT1 or a zinc finger mutant form, DDS (R394W), revealed significantly altered patterns of expression. Validation studies using quantitative real-time PCR confirmed the differential expression of the tumor progression gene, vascular endothelial growth factor (VEGF). WT1-LNCaP cells had significantly reduced levels of VEGF mRNA when compared to vector control cells; in contrast, DDS-LNCaP cells showed elevated levels of VEGF transcripts. To address a functional role for WT1 overexpression, we investigated whether induction of VEGF expression, by the synthetic androgen R1881, would be disrupted in wild-type or mutant WT1-transfected LNCaP cells. Hormone treatment failed to elevate VEGF transcript levels above uninduced baseline levels in WT1-LNCaP cells, despite 48 h of treatment with 5 nM R1881. Consistent with our quantitative real-time PCR analysis, immunofluorescent staining of VEGF protein was reduced in WT1-LNCaP cells in both the presence and absence of R1881 treatment. Conversely, VEGF levels increased in vector control and DDS-LNCaP cells treated with 5 nM R1881. Not only do these studies point out the regulatory potential of WT1 for VEGF, but they also indicate an altered function for the mutant DDS isoform. Because VEGF is associated with neovascularization and promotion of metastasis in a variety of solid tumors including prostate cancer, a better understanding of the regulation of VEGF expression by transcription factors, such as WT1, is important for halting disease progression.
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PMID:Vascular endothelial growth factor (VEGF) is suppressed in WT1-transfected LNCaP cells. 1657 86

Photodynamic therapy (PDT) is now an approved therapeutic modality, and induction of vascular endothelial growth factor (VEGF) following subcurative PDT is of concern as VEGF may provide a survival stimulus to tumors. The processes that limit the efficacy of PDT warrant investigation so that mechanism-based interventions may be developed. This study investigates VEGF increase following subcurative PDT using the photosensitizer benzoporphyrin derivative (BPD) both in an in vitro and in an orthotopic model of prostate cancer using the human prostate cancer cell line LNCaP. The two subcurative doses used, 0.25 and 0.5 J/cm(2), mimicked subcurative PDT and elicited a 1.6- and 2.1-fold increase, respectively, in secreted VEGF 24 hours following PDT. Intracellular VEGF protein measurement and VEGF mRNA showed a 1.4- and 1.6-fold increase only at 0.5 J/cm(2). In vivo subcurative PDT showed an increase in VEGF by both immunohistochemistry and ELISA. In vitro analysis showed no activation of hypoxia-inducible factor-1alpha (HIF-1alpha) or cyclooxygenase-2 (COX-2) following subcurative PDT; furthermore, small interfering RNA inhibition of HIF-1alpha and COX-2 inhibitor treatment had no effect on PDT induction of VEGF. PDT in the presence of phosphatidylinositol 3-kinase/AKT inhibitor or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase inhibitor still induced VEGF. However, subcurative PDT increased phosphorylated p38 and stress-activated protein kinase/c-Jun NH(2)-terminal kinase. The p38 MAPK inhibitor abolished PDT induction of VEGF. The results establish the importance of VEGF in subcurative BPD-PDT of prostate cancer and suggest possible molecular pathways for its induction. These findings should provide the basis for the development of molecular-based interventions for enhancing PDT and merit further studies.
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PMID:Mechanistic investigation and implications of photodynamic therapy induction of vascular endothelial growth factor in prostate cancer. 1674 Jul

The integration of imaging technologies with the capabilities of genetic engineering has created novel opportunities for understanding and imaging cancer. Here, we have combined vascular magnetic resonance imaging (MRI) and optical imaging to understand the relationship between hypoxia and vascularization in a human prostate cancer model engineered to express enhanced green fluorescent protein (EGFP) under hypoxia. Characterization and validation of EGFP expression under hypoxic conditions was done in culture and in solid tumors in vivo. MRI measurements showed that vascular volume was significantly lower in fluorescing regions. These regions also frequently exhibited high permeability. These data were further supported by the detection of low vessel density in EGFP-positive regions, as determined by the distribution of intravascularly administered, fluorescence-labeled Lycopersicon esculentum lectin in frozen tumor sections. These observations are consistent with the possibility that regions of low vascular volumes are hypoxic, which induces increased expression of functionally active vascular endothelial growth factor, a potent vascular permeability factor.
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PMID:Characterizing vascular parameters in hypoxic regions: a combined magnetic resonance and optical imaging study of a human prostate cancer model. 1704 55

Vascular endothelial growth factor (VEGF) is a proangiogenic factor upregulated in many tumors. The alternative splicing of VEGF mRNA renders 3 major isoforms of 121, 165 and 189 amino-acids in humans (1 less amino-acid for each mouse VEGF isoform). We have designed isoform specific real time QRT-PCR assays to quantitate VEGF transcripts in mouse and human normal and malignant prostates. In the human normal prostate, VEGF(165) was the predominant isoform (62.8% +/- 5.2%), followed by VEGF(121) (22.5% +/- 6.3%) and VEGF(189) (p < 0.001) (14.6% +/- 2.1%). Prostate tumors showed a significant increase in the percentage of VEGF(121) and decreases in VEGF(165) (p < 0.01) and VEGF(189) (p < 0.05). However, the amount of total VEGF mRNA was similar between normal and malignant prostates. VEGF(164) was the transcript with the highest expression in the mouse normal prostate. Unlike human prostate cancer, tumors from TRAMP mice demonstrated a significant increase in total VEGF mRNA levels and in each of the VEGF isoforms, without changes in the relative isoform ratios. Morpholino phosphorodiamide antisense oligonucleotide technology was used to increase the relative amount of VEGF(121) while proportionally decreasing VEGF(165) and VEGF(189) levels in human prostate cell lines, through the modification of alternative splicing, without changing transcription levels and total amount of VEGF. The increase in the VEGF(121)/VEGF(165-189) ratio in PC3 cells resulted in a dramatic increase in prostate tumor angiogenesis in vivo. Our results underscore the importance of VEGF(121) in human prostate carcinoma and demonstrate that the relative expression of the different VEGF isoforms has an impact on prostate carcinogenesis.
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PMID:Increased expression of VEGF121/VEGF165-189 ratio results in a significant enhancement of human prostate tumor angiogenesis. 1727 99

To identify physiologically relevant WT1 transcriptional target genes in prostate cancer cells, we have established stably transfected LNCaP cell lines expressing either WT1(A), its mutant counterpart DDS(R384W), or vector control. Microarray analyses of these cells revealed that vascular endothelial growth factor (VEGF) was differentially expressed in the engineered lines. Regulation of VEGF by WT1 likely contributes to kidney angiogenesis during development and WT1 mutants such as DDS(R384W) are associated with the Denys-Drash syndrome (DDS), characterized by renal abnormalities. Recent mechanistic studies have demonstrated that the WT1(A) isoform binds VEGF promoter sequences and transcriptionally regulates VEGF reporter constructs. However, regulation of VEGF is complex, involving both transcriptional and post-transcriptional processes. This study examined the ability of hormone and Actinomycin D treatment to alter VEGF mRNA levels in stably transfected WT-LNCaP, DDS-LNCaP, or V-LNCaP prostate cancer cells. The rationale of this study was based on a previous finding that enhancement of VEGF expression in DDS-LNCaP cells occurred only in the presence of the androgen analog, R1881. One possible explanation for these results was that DDS-WT1 stabilized VEGF mRNA so that it accumulated to higher levels. This hypothesis was tested by treating engineered LNCaP cells with Actinomycin D (Act D) and then measuring VEGF mRNA levels by quantitative real-time PCR. The combined effects of WT1 or DDS(R384W) and hormone were tested in these message stability assays and also in transcription assays of transiently transfected LNCaP cells. The results indicated that DDS-WT1 is unable to regulate VEGF transcription or stabilize VEGF mRNA in LNCaP prostate cancer cells. However our observations are also consistent with wild-type WT1(A) having both transcriptional and post-transcriptional effects on VEGF mRNA levels in the presence of hormone. These studies of VEGF regulation by WT1 and dysregulation by DDS(R384W) suggest an important role for WT1 in both normal and tumor-related angiogenesis.
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PMID:VEGF transcription and mRNA stability are altered by WT1 not DDS(R384W) expression in LNCaP cells. 1748 99

Human studies suggest that excessive energy intake and obesity may influence prostate cancer progression. Rodent experiments demonstrate that diet restriction attenuates tumor growth in parallel with reduced vascular density. The present study examines changes in the insulin-like growth factor I (IGF-I) axis caused by dietary restriction and their association with the expression of vascular endothelial growth factor (VEGF) in prostate cancer. Weanling male Copenhagen rats were randomized into control or 40% dietary restricted groups (n = 5). After 8 wk, rats were implanted with rat AT6.3 prostate adenocarcinoma cells. Two weeks later, the animals were sacrificed and serum, normal prostate, liver, and prostate tumor samples were collected for analyses. Dietary restriction reduced serum concentrations of IGF-I by 35% (P < 0.05) and increased IGF-binding protein-3 (IGFBP3) by sevenfold (P < 0.0001). Lower circulating IGF-I concentrations were correlated with reduced IGF-I mRNA expression in the liver, the primary source of circulating IGF-I. Dietary restriction also lowered mRNA expression of IGF-I (45%, P = 0.0242) and its receptor IGFIR (40%, P = 0.0083) in prostate tumors. Similarly, reduced VEGF mRNA (30%, P = 0.0176) and secreted VEGF protein (33%, P = 0.0003) were observed in prostate cancer of restricted rats. An in vitro study employing AT6.3 prostate cancer cells demonstrated dose- and time-dependent stimulation of VEGF expression by IGF-I. These results suggest that dietary restriction reduces endocrine and prostate tumor autocrine/paracrine IGF-I expression, which contributes to reduced VEGF expression and signaling, to inhibit tumor angiogenesis associated with prostate tumorigenesis.
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PMID:Interrelationships between dietary restriction, the IGF-I axis, and expression of vascular endothelial growth factor by prostate adenocarcinoma in rats. 1805 7

The enzyme 15-lipoxygenase-2 (15-LOX-2) utilizes arachidonic acid, a polyunsaturated fatty acid, to synthesize 15(S)-hydroxyeicosatetraenoic acid. Abundantly expressed in normal prostate epithelium but frequently suppressed in the cancerous tissues, 15-LOX-2 has been suggested as a functional suppressor of prostate cancer, but the mechanism(s) involved remains unknown. To study the functional role of 15-LOX-2 in prostate cancer, we expressed 15-LOX-2 as a fusion protein with GFP in DU145 and PC-3 cells and found that 15-LOX-2 increased cell cycle arrest at G0/G1 phase. When injected into athymic nu/nu mice, prostate cancer cells with 15-LOX-2 expression could still form palpable tumors without significant changes in tumorigenicity. But, the tumors with 15-LOX-2 expression grew significantly slower than those derived from vector controls and were kept dormant for a long period of time. Histological evaluation revealed an increase in cell death in tumors derived from prostate cancer cells with 15-LOX-2 expression, while in vitro cell culture conditions, no such increase in apoptosis was observed. Further studies found that the expression of vascular endothelial growth factor A (VEGF-A) was significantly reduced in prostate cancer cells with 15-LOX-2 expression restored. Our studies suggest that 15-LOX-2 suppresses VEGF gene expression and sustains tumor dormancy in prostate cancer. Loss of 15-LOX-2 functionalities, therefore, represents a key step for prostate cancer cells to exit from dormancy and embark on malignant progression in vivo.
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PMID:Downregulation of vascular endothelial growth factor and induction of tumor dormancy by 15-lipoxygenase-2 in prostate cancer. 1908 21


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