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)

Osteoprotegerin (OPG), a key regulator of bone resorption, is hypothesized to have a role in prostate cancer (CaP) bone metastasis. As advanced CaP is treated by androgen ablation, we examined if androgen modulates OPG expression by CaP cell lines in vitro. Basal levels of secreted OPG protein were significantly greater in androgen-independent PC-3 cells compared with androgen-responsive LNCaP-FGC cells (P<0.001); OPG was not detected in the androgen-responsive CaP cell lines LAPC-4 or DuCaP. Treatment with 5alpha-dihydrotestosterone (5alpha-DHT) significantly decreased OPG protein levels in both PC-3 and LNCaP-FGC, with maximal suppression using 10(-9)-10(-7) M 5alpha-DHT in PC-3 (P<0.01; day 3), and using 10(-10)-10(-9) M 5alpha-DHT in LNCaP-FGC cells (P<0.01; day 6). OPG messenger RNA levels were not significantly altered by this 5alpha-DHT treatment. Co-treatment with 10(-6) M flutamide blocked 5alpha-DHT inhibition of OPG protein expression in LNCaP-FGC cells. These data suggest that androgen may modulate OPG protein levels in CaP cell lines in vitro using a post-transcriptional mechanism.
Prostate Cancer Prostatic Dis 2007
PMID:Androgen decreases osteoprotegerin expression in prostate cancer cells. 1718 57

Prostate cancer metastases to bone are observed in around 80% of prostate cancer patients and represent the most critical complication of advanced prostate cancer, frequently resulting in significant morbidity and mortality. As the underlying mechanisms are not fully characterized, understanding the biological mechanisms that govern prostate cancer metastases to bone at the molecular level should lead to the determination of new potential therapeutic targets. Receptor activator of NFkappaB ligand (RANKL)/RANK/Osteoprotegerin (OPG) are the key regulators of bone metabolism both in normal and pathological condition, including prostate cancer bone metastases. In the present study, we demonstrated that human prostate cancer cell lines, DU145 and PC3 express biologically functional RANK. Indeed, soluble human RANKL (shRANKL, 100 ng/ml) treatment induced ERK 1/2, p38 and IkappaB phosphorylations in these cells. shRANKL administration also promoted DU145 and PC3 prostate cancer cell invasion in vitro. Whereas human OPG (hOPG) administration alone (100 ng/ml) had no marked effect, combined association of both agents abolished the RANKL-induced DU145 cell invasion. As RANKL had no direct effect on DU145 cell proliferation, the observed effects were indeed related to RANKL-induced cell migration. DU145 human prostate cancer cells promoted osteoclastogenesis of osteoclast precursors generated from mouse bone marrow. Moreover, DU145 cells produced soluble factor(s) that up-regulate the proliferation of MC3T3-E1 pre-osteoblasts through the activation of the ERK 1/2 and STAT3 signal transduction pathways. This stimulation of pre-osteoblast proliferation resulted in an increased local RANKL expression that can activate both osteoclasts/osteoclast precursors and prostate cancer cells, thus facilitating prostate cancer metastasis development in bone. We confirm that RANKL is a factor that facilitates metastasis to bone by acting as an activator of both osteoclasts and RANK-positive prostate cancer cells in our model. Furthermore, the present study provides the evidence that blocking RANKL-RANK interaction offer new therapeutic approach not only at the level of bone resorbing cells, but also by interfering with RANK-positive prostate cancer cells in the prostate cancer bone metastasis development.
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PMID:DU145 human prostate cancer cells express functional receptor activator of NFkappaB: new insights in the prostate cancer bone metastasis process. 1719 95

The role of receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) system, and osteopontin (OPN) was studied in patients with solid tumors metastatic to the bone in relation to the type of malignancy and the neoplastic burden to the skeleton. Levels of soluble RANKL (sRANKL), OPG and OPN were assessed in 61 patients with breast, lung and prostate cancer with newly-diagnosed metastasis to the bone, in parallel with bone resorption [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase-5b (TRACP-5b)] and bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP)]. Patients had elevated serum levels of sRANKL, OPG, OPN, TRACP-5b, and bALP, and reduced OC levels compared to controls. OPG correlated with the extent of metastatic bone burden. Patients with breast and lung cancer shared increased levels of sRANKL, OPG, and OPN whereas prostate cancer patients had elevated values of OPG and bALP only. These results suggest that patients with solid tumors metastatic to the bone have severe disruption of the sRANKL/OPG axis. Breast and lung cancer seem to exert their osteolytic action through upregulation of the sRANKL/OPG system and OPN, whereas prostate cancer seems to provoke profound elevation of OPG levels only, thus leading to increased osteoblastic activity.
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PMID:Abnormal bone remodeling process is due to an imbalance in the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) axis in patients with solid tumors metastatic to the skeleton. 1745 73

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a major mediator of collagen I degradation. In human samples, we show that prostate cancer cells in skeletal metastases consistently express abundant MT1-MMP protein. Because prostate cancer bone metastasis requires remodeling of the collagen-rich bone matrix, we investigated the role of cancer cell-derived MT1-MMP in an experimental model of tumor-bone interaction. MT1-MMP-deficient LNCaP human prostate cancer cells were stably transfected with human wild-type MT1-MMP (MT1wt). Furthermore, endogenous MT1-MMP was down-regulated by small interfering RNA in DU145 human prostate cancer cells. Intratibial tumor injection in severe combined immunodeficient mice was used to simulate intraosseous growth of metastatic tumors. LNCaP-MT1wt cells produced larger osseous tumors than Neo control cells and induced osteolysis, whereas DU145 MT1-MMP-silenced transfectants induced osteogenic changes. In vitro assays showed that MT1wt overexpression enhanced collagen I degradation, whereas MT1-MMP-silencing did the opposite, suggesting that tumor-derived MT1-MMP may contribute directly to bone remodeling. LNCaP-MT1wt-derived conditioned medium stimulated in vitro multinucleated osteoclast formation. This effect was inhibited by osteoprotegerin, a decoy receptor for receptor activator of nuclear factor kappaB ligand, and by 4-[4-(methanesulfonamido) phenoxy] phenylsulfonyl methylthiirane, an MT1-MMP inhibitor. Our findings are consistent with the hypothesis that prostate cancer-associated MT1-MMP plays a direct and/or indirect role in bone matrix degradation, thus favoring intraosseous tumor expansion.
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PMID:Prostate cancer-associated membrane type 1-matrix metalloproteinase: a pivotal role in bone response and intraosseous tumor growth. 1752 76

A commonly used monoclonal antibody targeting osteoprotegerin (OPG), MAB8051, detects a truncated protein species in breast and prostate cancer cell lysates. OPG expression has been reported to contribute to cell survival of both of these cancers. We hypothesised that the truncated protein represented a unique tumour-associated OPG isoform. However, here we show that the truncated protein identified by MAB8051 in cancer cell lines is carbonic anhydrase II (CA II), also implicated in tumour biology. We clearly demonstrate cross-reactivity of this OPG antibody in western blots. OPG and CA II RNA-interference studies confirmed the identity of the bands. We show almost identical staining patterns between MAB8051 and CA II immunohistochemistry of different human tissue types and human tumour types using serial sections. We conclude that care should be exercised using this antibody for immunohistochemistry studies, without additional in situ hybridisation, or parallel use of other OPG-specific antibodies.
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PMID:The antibody MAB8051 directed against osteoprotegerin detects carbonic anhydrase II: implications for association studies with human cancers. 1763 39

Prostate cancers frequently metastasize to the skeleton, and it has been hypothesized that this environment selectively supports the growth of these tumours. Specifically there is strong evidence that interactions between tumour cells and BMSCs (bone marrow stromal cells) play a major role in supporting prostate cancer growth and survival in bone. Here, we examine factors shown to be secreted by BMSCs, such as IGFs (insulin-like growth factors) and IL-6 (interleukin 6), shown to promote prostate cancer cell proliferation and to potentially replace the requirement for androgens. In addition we discuss another factor produced by BMSCs, osteoprotegerin, which may promote tumour cell survival by suppressing the biological activity of the pro-apoptotic ligand TRAIL (tumour-necrosis-factor-related apoptosis-inducing ligand).
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PMID:Bone marrow stromal cells promote growth and survival of prostate cancer cells. 1763 26

Factors that regulate the induction of apoptosis of tumour cells are potential candidates for therapeutic intervention for the majority of cancers. Studying modifiers of apoptotic responses, such as members of the tumour necrosis factor receptor superfamily, may give clues as to how induction of apoptosis in tumours could be maximized to enhance the benefit of treatment regimes. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-tumour molecule since its activity is specific for tumour cell populations. TRAIL binds to death receptors, inducing apoptosis in susceptible cells. The mechanisms which determine whether tumour cells are susceptible to TRAIL are unclear, and several mechanisms have been proposed, including expression of osteoprotegerin (OPG), decoy receptors, and factors that affect intracellular signalling of pro-apoptotic molecules, such as c-FLIP. Here we show that experiments to modulate the activity of one of these factors, OPG, by over-expression and also by stable knockdown of OPG expression, alters the TRAIL sensitivity of PC3 prostate cancer cells. However we show that some observed effects, which appear to support the hypothesis that OPG prevents TRAIL-induced apoptosis of tumour cells, may be due to variation of the TRAIL response of sub-clones of tumour cells, even within a cloned population. These results highlight potential limitations of experiments designed to test contribution of factors affecting intrinsic apoptosis susceptibility using cloned tumour cell populations.
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PMID:Phenotypic variations of TRAIL sensitivity in cloned populations of prostate cancer cells. 1832 May 83

Tumor cells induce excessive osteoclastogenesis, mediating pathologic bone resorption and subsequent release of growth factors and calcium from bone matrix, resulting in a "vicious cycle" of bone breakdown and tumor proliferation. RANK ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. In metastatic prostate cancer models, RANKL inhibition directly prevents osteolysis via blockade of osteoclastogenesis and indirectly reduces progression of skeletal tumor burden by reducing local growth factor and calcium concentrations. Docetaxel, a well-established chemotherapy for metastatic hormone-refractory prostate cancer, arrests the cell cycle and induces apoptosis of tumor cells. Suppression of osteoclastogenesis through RANKL inhibition may enhance the effects of docetaxel on skeletal tumors. We evaluated the combination of the RANKL inhibitor osteoprotegerin-Fc (OPG-Fc) with docetaxel in a murine model of prostate cancer bone metastasis. Tumor progression, tumor area, and tumor proliferation and apoptosis were assessed. OPG-Fc alone reduced bone resorption (P < 0.001 versus PBS), inhibited progression of established osteolytic lesions, and reduced tumor area (P < 0.0001 versus PBS). Docetaxel alone reduced tumor burden (P < 0.0001 versus PBS) and delayed the development of osteolytic lesions. OPG-Fc in combination with docetaxel suppressed skeletal tumor burden (P = 0.0005) and increased median survival time by 16.7% (P = 0.0385) compared with docetaxel alone. RANKL inhibition may enhance docetaxel effects by increasing tumor cell apoptosis as evident by increased active caspase-3. These studies show that inhibition of RANKL provides an additive benefit to docetaxel treatment in a murine model of prostate cancer bone metastasis and supports clinical evaluation of this treatment option in patients.
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PMID:RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis. 1860 16

Osteoprotegerin (OPG), member of tumor necrosis factor (TNF) receptor superfamily, has various biological functions including bone remodeling. OPG binds to receptor activator of nuclear factor-kB ligand (RANKL) and prevents osteoclastic bone resorption. Recently, OPG has gained more clinical interest as its role in cancer-mediated bone destruction and the potential of RANKL inhibition could act as a novel treatment in tumor-induced bone disease. OPG protects prostate cancer cells from apoptotic effects of TRAIL and therefore provides tumor cells producing OPG with survival advantages. Additionally, the increased RANKL/OPG ratio in metastatic breast cancer results in severe osteolysis. Thus, bone formation and resorption are the crux of cancer metastasis, resulting in bone pain and pathological fractures. This review provides an overview of the role of OPG in cancer-induced bone disease.
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PMID:Mechanism of bone metastasis: the role of osteoprotegerin and of the host-tissue microenvironment-related survival factors. 1920 Oct 81

Glucocorticoids (GCs) are widely used for the treatment of hormone refractory prostate cancer. However, few data are available on the expression and regulation of glucocorticoid and mineralocorticoid receptors (GR and MR) and 11beta-hydroxysteroid dehydrogenase (11beta-HSD) 1 and -2 activities in prostate cancer cells. Here we show that GR is expressed in both the androgen-independent PC-3 cell line and, at very low levels, in the androgen-dependent LNCaP cells, and MR is expressed in both cell lines. IL-1beta increased GR expression in both cell lines. In LNCaP cells IL-1beta also increased MR expression. Significant 11beta-HSD oxidase activity and 11beta-HSD2 protein were found in LNCaP cells, but not in PC3 cells, and no ketoreductase activity was detected in either cell lines. GR function was assessed by measuring the inhibitory effect of dexamethasone on constitutive and IL-1beta-inducible IL-6 and osteoprotegerin (OPG) production. In PC-3 cells, IL-1beta stimulated IL-6 and OPG release, and dexamethasone dose-dependently inhibited IL-1beta-inducible IL-6 release, and constitutive and IL-1beta-inducible OPG release. In LNCaP cells, IL-1beta stimulated only OPG release. While dexamethasone was ineffective, cortisol dose-dependently inhibited IL-1beta-inducible OPG release. Eplerenone (Epl), a selective mineralocorticoid antagonist, reverted this effect. We conclude that different patterns of expression of receptors and 11beta-HSD activity were associated with different responsiveness to GCs in terms of regulated gene expression. GR and MR expression may vary as a function not only of the malignant phenotype, but also of local conditions such as the degree of inflammation. Inhibition of IL-6 and OPG release by GCs may contribute to the antitumor efficacy in prostate cancer.
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PMID:Differential expression of determinants of glucocorticoid sensitivity in androgen-dependent and androgen-independent human prostate cancer cell lines. 1940 40


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