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)

Interleukin-6 (IL-6) is involved in regulation of immune reaction and cell growth and differentiation. It causes multifunctional responses ranging from inhibition of proliferation to promotion of cell survival. IL-6 effects may depend on experimental conditions such as passage numbers and serum composition. IL-6 signals in target tissues through the receptor that is composed of the ligand-binding and signal-transducing subunits. IL-6 is expressed in benign and malignant prostate tissue and the levels of the cytokine and its receptor increase during prostate carcinogenesis. IL-6 is considered a positive growth factor for most prostate cells. The only exemption seems to be the LNCaP cell line, in which IL-6 causes growth arrest and induces differentiation function. In contrast, IL-6 acts as an autocrine growth factor in the subline LNCaP-IL-6+ established after chronic treatment with IL-6. IL-6 is a candidate for targeted therapy in prostate cancer because of its association with morbidity. Activation of signaling pathways of Janus kinase/signal transducers and activators of transcription factors, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase has been reported in various prostate cancer cell lines. IL-6 and the related cytokine oncostatin M induce activation of the androgen receptor (AR) in the absence of androgen. IL-6 is also involved in regulation of vascular endothelial growth factor expression as well as neuroendocrine differentiation in prostate. Anti-IL-6 antibodies showed an inhibitory effect on the PC-3 xenograft. However, the development of this therapy in prostate cancer is in early stages.
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PMID:Interleukin-6 regulation of prostate cancer cell growth. 1583 76

Androgen ablation therapy is eventually followed by a more metastatic and androgen-refractory stage of prostate cancer. The detailed molecular mechanism of this gradual transition is not clearly understood. Recent reports correlate the high abundance of vascular endothelial growth factor-C (VEGF-C) to the lymph node metastasis seen in human prostate cancer (Tsurusaki et al., 1999). In this study, we report that androgen ablation in LNCaP cells augment the transcriptional upregulation of VEGF-C and the downregulation of the IGF-IR pathway, due to androgen withdrawal, is a potential mechanism for this observed VEGF-C transcription. Forkhead transcription factor FOXO-1, activated by SIRT-1, was identified as the downstream molecule within this pathway. Furthermore, the VEGF-C-induced increase of Bag-IL expression in LNCaP cells suggests that VEGF-C plays a role in the androgen-independent reactivation of the androgen receptor, resulting in androgen-refractory prostate cancer growth.
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PMID:Upregulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO pathway. 1589 88

Androgen-independent metastatic prostate cancer is the main cause of cancer related death in men. One of the reasons for this is the lack of understanding of the molecular mechanisms leading to the metastatic progression of prostate cancer. In this study, we have demonstrated that overexpression of Id-1 (inhibitor of differentiation/DNA synthesis), a member of the helix-loop-helix family proteins, is a key factor in promoting angiogenesis through activation of the vascular endothelial growth factor (VEGF) in prostate cancer cells. Using prostate cancer cells ectopically transfected with the Id-1 gene, we found that upregulation of Id-1 induced VEGF secretion through activation of the VEGF gene transcription. Downregulation of Id-1, however, led to the suppression of VEGF secretion and its gene promoter activity. The association between Id-1 and VEGF was also confirmed on human xenografts by immunohistochemical staining. In addition, the growth medium generated by the Id-1 expressing cells was able to promote morphological changes as well as capillary tube formation in human umbilical vein endothelial cells (HUVECs) at similar degrees to the recombinant human VEGF. Furthermore, inhibition of VEGF function by the treatment with an Flk-1 inhibitor, SU1498, or with the VEGF neutralizing antibody resulted in the reverse of the angiogenic effect on HUVECs. Our results suggest that overexpression of Id-1 in prostate cancer cells may provide an autocrine signal to promote angiogenesis through the activation of VEGF. Since increased Id-1 has been reported in many types of advanced human cancers, our results indicate that downregulation of Id-1 may be a novel target to inhibit the growth of metastatic cancers through the suppression of angiogenesis.
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PMID:Overexpression of Id-1 in prostate cancer cells promotes angiogenesis through the activation of vascular endothelial growth factor (VEGF). 1590 2

RNA interference technology is emerging as a very potent tool to obtain a cellular knockdown of a desired gene. In this work we used vector-based RNA interference to inhibit vascular endothelial growth factor (VEGF) expression in prostate cancer in vitro and in vivo. We demonstrated that transduction with a plasmid carrying a small interfering RNA targeting all isoforms of VEGF, dramatically impairs the expression of this growth factor in the human prostate cancer cell line PC3. As a consequence, PC3 cells loose their ability to induce one of the fundamental steps of angiogenesis, namely the formation of a tube-like network in vitro. Most importantly, our "therapeutic" vector is able to impair tumor growth rate and vascularization in vivo. We show that a single injection of naked plasmid in developing neoplastic mass significantly decreases microvessel density in an androgen-refractory prostate xenograft and is able to sustain a long-term slowing down of tumor growth. In conclusion, our results confirm the basic role of VEGF in the angiogenic development of prostate carcinoma, and suggest that the use of our vector-based RNA interference approach to inhibit angiogenesis could be an effective tool in view of future gene therapy applications for prostate cancer.
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PMID:Vector-based RNA interference against vascular endothelial growth factor-A significantly limits vascularization and growth of prostate cancer in vivo. 1595 82

The authors examined 25 patients with prostate cancer (PC) and 36 patients with benign prostatic hyperplasia (BPH). In the group of patients with morphologically verified PC mean serum level of vascular endothelial growth factor (VEGF) was significantly higher than in patients with BPH (p < 0.05). The study demonstrated strong negative association between VEGF and prostate specific antigen (PSA) levels (r = 0.72, p < 0.05) in PC patients. There was no association between VEGF serum level and the stage or malignancy of PC (Gleason score). In benign prostatic glands moderate VEGF expression was observed only in basal cells, whereas in cases of PC all tumor cells displayed active VEGF expression; the difference was significant (p < 0.05). High serum VEGF levels and its active expression in patients with PC suggest an important role of angiogenic factors in the pathogenesis of this disease. The negative association between VEGF and PSA serum levels in PC indirectly confirms antiangiogenic activity of PSA, shown before.
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PMID:[Vascular endothelial growth factor in patients with prostate cancer and benign prostatic hyperplasia]. 1596 Jan 97

Transforming growth factor beta (TGF-beta) is a multifunctional cytokine involved in the regulation of cell proliferation, differentiation and survival/or apoptosis of many cells. Knock-out experiments in mice for the three isoforms of TGF-beta have demonstrated their importance in regulating inflammation and tissue repair. TGF-beta is implicated in the pathogenesis of human diseases, including tissue fibrosis and carcinogenesis. TGF-beta receptors act through multiple intracellular pathways. Upon binding of TGF-beta with its receptor, receptor-regulated Smad2/3 proteins become phosphorylated and associate with Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of specific genes. Negative regulation of TGF-beta/Smad signalling may occur through the inhibitory Smad6/7. Furthermore, TGF-beta-activated kinase-1 (TAK1) is a component of TGF-beta signalling and activates stress-activated kinases: p38 through MKK6 or MKK3 and c-Jun N-terminal kinases (JNKs) via MKK4. In the brain TGF-beta, normally expressed at the very low level, increases dramatically after injury. Increased mRNA levels of the three TGF-beta isoforms correlate with the degree of malignancy of human gliomas. TGF-betas are secreted as latent precursors requiring activation into the mature form. TGF-beta may contribute to tumour pathogenesis by direct support of tumour growth and influence on local microenvironment, resulting in immunosuppression, induction of angiogenesis, and modification of the extracellular matrix. TGF-beta1,2 may stimulate production of vascular endothelial growth factor (VEGF) as well as plasminogen activator inhibitor (PAI-I), that are involved in vascular remodelling occurring during angiogenesis. Blocking of TGF-beta action inhibits tumour viability, migration, metastases in mammary cancer, melanoma and prostate cancer model. Reduction of TGF-beta production and activity may be a promising target of therapeutic strategies to control tumour growth.
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PMID:TGF beta signalling and its role in tumour pathogenesis. 1599 Sep 18

Elevated levels of cyclin A1 expression have been implicated in acute myeloid leukemia and in male germ cell tumors. However, a role of cyclin A1 in tumorigenesis of prostate cancer has not been reported. In the present study, expression of cyclin A1 in patients with prostate cancer and a role of cyclin A1 in mediating expression of vascular endothelial growth factor (VEGF) were investigated. Cyclin A1 was highly expressed in aggressive tumors and was significantly correlated with VEGF expression in 96 patients with prostate cancer. Treatment of LNCaP cells with R1881, a synthetic androgen resulted in increased cyclin A1 expression. Induction of cyclin A1 expression in LNCaP cells led to an increase in VEGF expression and this effect was manifested upon the R1881 treatment. Cyclin A1 failed to mediate VEGF activation in DU-145 cells lacking a functional Rb and an androgen receptor (AR). Although AR expression was induced into DU-145 cells, cyclin A1 was unable to mediate VEGF expression. However, induced coexpression of cyclin A1, Rb and AR in DU-145 cells in the presence of R1881 greatly promoted VEGF promoter activity. This suggests that cyclin A1 mediates VEGF expression in cooperation with Rb- and androgen-dependent pathways in prostate cancer.
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PMID:A role for cyclin A1 in mediating the autocrine expression of vascular endothelial growth factor in prostate cancer. 1600 89

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

The field of cancer research has seen a marked shift in the past decade towards the exploration and development of non-conventional antitumour agents. One of the most widely studied approaches to therapy during this period has been that of antiangiogenesis. The published clinical trials and subsequent FDA approval (in February 2004) of the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin, Genentech) for the treatment of colorectal cancer marked a milestone for antiangiogenesis therapy. Currently, preclinical and clinical research involving therapeutic targeting of VEGF and other mediators of angiogenesis continues in multiple tumour types. In addition to colorectal cancer, angiogenesis inhibitors are being investigated in the treatment of renal cell carcinoma, head and neck carcinoma, lung cancer, breast cancer, prostate cancer, and a variety of haematological malignancies. This article will discuss the background of antiangiogenesis research, preclinical and clinical data relating to the use of bevacizumab in the treatment of colorectal cancer, other completed clinical trials involving antiangiogenesis agents, and the potential future utility of these agents in the treatment of malignancy.
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PMID:Angiogenesis inhibitors in the treatment of cancer. 1608 56

The Runx2 (Cbfa1/AML3) transcription factor and matrix metalloproteinase 9 (MMP9) are key regulators of growth plate maturation and bone formation. The genes for both proteins are characteristic markers of breast and prostate cancer cells that metastasize to bone. Here we experimentally addressed the compelling question of whether Runx2 and MMP are functionally linked. By cDNA expression array analysis, we identified MMP9 as a novel downstream target of Runx2. Like that of MMP13, MMP9 expression is nearly depleted in Runx2 mutant mice. Chromatin immunoprecipitation and electrophoretic mobility shift assays revealed the recruitment of Runx2 to the MMP9 promoter. We show by mutational analysis that the Runx2 site mediates transactivation of the MMP9 promoter in osteoblasts (MC3T3-E1) and nonosseous (HeLa) cells. The overexpression of Runx2 by adenovirus delivery in nonmetastatic (MCF-7) and metastatic breast (MDA-MB-231) and prostate (PC3) cancer cell lines significantly increases the endogenous levels of MMP9. The knockdown of Runx2 by RNA interference decreases MMP9 expression, as well as that of other Runx2 target genes, including the genes for MMP13 and vascular endothelial growth factor. Importantly, we have demonstrated using a cell invasion assay that Runx2-regulated MMP9 levels are functionally related to the invasion properties of cancer cells. These results are consistent with Runx2 control of multiple genes that contribute to the metastatic properties of cancer cells and their activity in the bone microenvironment.
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PMID:The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion. 1616 39


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