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)

Serum insulin-like growth factor-I (IGF-I) levels at the higher end of the reference range have been associated with increased risk for the future development of prostate cancer. We determined whether high serum IGF-I levels are associated with precancerous lesions of the prostate. We conducted a case-control study to determine whether high serum IGF-I levels were associated with the presence of high-grade prostatic intraepithelial neoplasia (HGPIN) among patients who presented for prostate biopsy because of an abnormal serum prostate-specific antigen level or digital rectal exam. We measured serum IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) prior to prostate biopsy and compared them between 103 men with HGPIN (cases) and 205 men with normal prostate histology (controls). The mean IGF-I level in patients with HGPIN (130.2 ng/mL) was significantly higher compared with controls (118.8 ng/mL, P = 0.01). The mean IGFBP-3 level in patients with HGPIN (2,393.9 ng/mL) was also higher compared with controls (2,276.0 ng/mL, P = 0.06). After adjusting for age, prostate-specific antigen, digital rectal examination, and ethnic background, the odds ratio for a HGPIN diagnosis among men in the highest relative to the lowest quartile of serum IGF-I level was 1.94 (95% confidence interval, 1.0-3.7; P = 0.04). The potential association between a high serum IGF-I level and the presence of HGPIN may represent an important clue to understanding the basis for the relationship between IGF-I physiology and prostate cancer risk. Larger studies will be required to confirm this relationship.
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PMID:Serum insulin-like growth factor-I levels and prostatic intraepithelial neoplasia: a clue to the relationship between IGF-I physiology and prostate cancer risk. 1589 84

Prostate cancer is the most common cancer in men. Advanced prostate cancer spreading beyond the gland is incurable. Identifying factors that regulate the spread of tumor into the regional nodes and distant sites would guide the development of novel diagnostic, prognostic, and therapeutic targets. The aim of our study was to examine the expression and biological role of EphB4 in prostate cancer. EphB4 mRNA is expressed in 64 of 72 (89%) prostate tumor tissues assessed. EphB4 protein expression is found in the majority (41 of 62, 66%) of tumors, and 3 of 20 (15%) normal prostate tissues. Little or no expression was observed in benign prostate epithelial cell line, but EphB4 was expressed in all prostate cancer cell lines to varying degrees. EphB4 protein levels are high in the PC3 prostate cancer cell line and several folds higher in a metastatic clone of PC3 (PC3M) where overexpression was accompanied by EphB4 gene amplification. EphB4 expression is induced by loss of PTEN, p53, and induced by epidermal growth factor/epidermal growth factor receptor and insulin-like growth factor-I/insulin-like growth factor-IR. Knockdown of the EphB4 protein using EphB4 short interfering RNA or antisense oligodeoxynucleotide significantly inhibits cell growth/viability, migration, and invasion, and induces apoptosis in prostate cancer cell lines. Antisense oligodeoxynucleotide targeting EphB4 in vivo showed antitumor activity in murine human tumor xenograft model. These data show a role for EphB4 in prostate cancer and provide a rationale to study EphB4 for diagnostic, prognostic, and therapeutic applications.
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PMID:EphB4 expression and biological significance in prostate cancer. 1593 Feb 80

We have previously identified the retinoid X receptor-alpha (RXRalpha) as an insulin-like growth factor binding protein-3 (IGFBP-3) nuclear binding partner, which is required for IGFBP-3-induced apoptosis. In the current study, we investigated the biological interactions of the RXR ligand, VTP194204 and rhIGFBP-3, in vitro and in vivo. In vitro, IGFBP-3 and VTP194204 individually induced apoptosis, and suppressed cell growth in prostate cancer cell lines in an additive manner. In vivo, LAPC-4 xenograft-bearing severe combined immunodeficiency mice treated daily with saline, IGFBP-3, and/or VTP194204 for 3 weeks showed no effect of individual treatments with IGFBP-3 or VTP194204 on tumor growth. However, the combination of IGFBP-3 and VTP194204 treatments inhibited tumor growth by 50% and induced a significant reduction in serum prostate-specific antigen levels. In terminal nucleotidyl transferase-mediated nick end labeling immunohistochemistry of LAPC-4 xenografts, there was modest induction of apoptosis with either IGFBP-3 or VTP194204 individual treatment, but combination therapy resulted in massive cell death, indicating that IGFBP-3 and VTP194204 have a synergistic effect in preventing tumor growth by apoptosis induction. In summary, this is an initial description of the successful therapeutic use of IGFBP-3 as a cancer therapy in vivo, and shows that combination treatment of IGFBP-3 and RXR ligand has a synergistic effect on apoptosis induction leading to substantial inhibition of prostate cancer xenograft growth. Taken together, these observations suggest that combination therapy with IGFBP-3 and RXR ligands may have therapeutic potential for prostate cancer treatment.
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PMID:Combination therapy of insulin-like growth factor binding protein-3 and retinoid X receptor ligands synergize on prostate cancer cell apoptosis in vitro and in vivo. 1600 May 83

Prostate cancer is the most common urologic malignancy involving multiple factors. There is evidence that suggests that detoxification enzymes and growth factors may play a role in the formation of prostate cancer. Our aim was to investigate whether polymorphisms of glutathione S-transferase M1 (GST M1), insulin-like growth factor-2 (IGF-2), and epidermal growth factor (EGFR) genes could be used as genetic markers for risk of prostate cancer. In this study, we compared the frequency of the polymorphisms of GST M1, IGF-2, and EGFR genes among 96 patients with prostate cancer and 121 healthy male volunteers from the same geographic area (age, older than 60 years). There was significant difference in the GST M1 genotype between the prostate cancer group and the control group (P=0.042). The GST M1 null genotype was significantly higher in the cancer group (59.4%) than in the control group (45.5%). However, our study did not reveal a significant association between prostate cancer and the distribution of the IGF-2 or EGFR genotypes. This study suggests that the GST M1 gene, but not the IGF-2 or the EGFR genes, may be a risk factor of developing prostate cancer in Taiwan.
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PMID:Glutathione S-transferase M1 gene but not insulin-like growth factor-2 gene or epidermal growth factor gene is associated with prostate cancer. 1601 36

The cells' ability to proliferate in response to growth factor stimulation is significantly altered during cancer progression. To investigate the mechanisms underlying these alterations in prostate cancer, the role and expression of beta1A integrin and type 1 insulin-like growth factor receptor (IGF-IR), known to contribute to cell proliferation and transformation, were analyzed. Using small interfering RNA oligonucleotides to down-regulate beta1A, we show that beta1A expression is required for IGF-IR-mediated prostate cancer cell proliferation and anchorage-independent growth. In vivo, using age-matched transgenic adenocarcinoma of mouse prostate (TRAMP) mice at different stages of prostate cancer [prostatic intraepithelial neoplasia, PIN; well-differentiated adenocarcinoma, WD; and poorly differentiated adenocarcinoma, PD], the expression of beta1A and of IGF-IR was studied. beta1A and IGF-IR expression levels were concurrently up-regulated in high PIN and WD, whereas their expression did not correlate in late-stage PD. In contrast to the up-regulated expression of beta1A, the levels of beta1C, a beta1 cytoplasmic variant that inhibits cell proliferation, were down-regulated in all stages of prostate cancer. A similar expression pattern was observed for a beta1C downstream effector, Grb2-associated binder-1 (Gab1) which is known to inhibit IGF-IR phosphorylation. To analyze in vitro the mechanistic implications of beta1A, beta1C, and Gab1 deregulation in prostate cancer, we investigated whether expression of either beta1 variant in beta1-null cells affected IGF-IR localization. We found that IGF-IR and beta1A were colocalized in highly specialized integrin signaling compartments, designated focal contacts. However, in the presence of beta1C, IGF-IR remained diffuse on the cell surface and did not localize to focal contacts. The findings that beta1 integrins and IGF-IR are concurrently deregulated and that expression of beta1 integrins is necessary to achieve appropriate IGF-IR intracellular distribution point to the important role that the cross-talk between these receptors may have during prostate cancer progression and will be helpful in formulating new therapeutic strategies.
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PMID:beta1A integrin expression is required for type 1 insulin-like growth factor receptor mitogenic and transforming activities and localization to focal contacts. 1606 50

Epidemiological studies suggest that environmental factors may mediate the transformation of latent prostate cancer into clinically apparent tumors and that diet appears to influence this progression. Close correlations between average per capita fat intake and prostate cancer mortality internationally generated interest in underlying mechanisms for this link, such as through serum levels of androgens, free radicals, proinflammatory fatty acid metabolites, or insulin-like growth factor. Much interest currently lies in the potential of HMG-CoA reductase inhibitors (statins) to play a chemopreventative role in prostate cancer. Lycopene, a potent antioxidant found in tomatoes, may exert a protective effect in the prostate. Selenium and vitamin E have also been shown to decrease the risk of prostate cancer in some men. Calcium may support vitamin D-related antiproliferative effects in prostate cancer. Certain soy proteins, common in the Asian diet, have been shown to inhibit prostate cancer cell growth. Finally, green tea may also have a chemopreventive effect by inducing apoptosis. Despite confounding factors present in clinical studies assessing the effect of diet on cancer risk, the data remain compelling that a variety of nutrients may prevent the development and progression of prostate cancer.
Prostate Cancer Prostatic Dis 2005
PMID:Impact of diet on prostate cancer: a review. 1613 15

We have shown previously that apoptosis induction by diallyl trisulfide (DATS), a constituent of processed garlic, in PC-3 and DU145 human prostate cancer cells is associated with c-Jun N-terminal kinase and extracellular signal-regulated kinase-mediated phosphorylation of Bcl-2. However, pharmacological inhibition of these kinases offers only partial protection against the cell death caused by DATS. Here, we demonstrate that DATS inactivates Akt to trigger apoptosis in prostate cancer cells. Treatment of PC-3/DU145 cells with apoptosis inducing concentration of DATS (40 microM) resulted in a rapid decrease in Ser(473) and Thr(308) phosphorylation of Akt leading to inhibition of its kinase activity. The DATS-mediated inactivation of Akt was associated with downregulation of insulin-like growth factor receptor 1 protein level and inhibition of its autophosphorylation. DATS treatment (40 microM) also caused a decrease in Ser(155) and Ser(136) phosphorylation of BAD (a proapoptotic protein), which is a downstream target of Akt. Phosphorylation sequesters BAD in the cytoplasm owing to increased binding with 14-3-3 proteins. The interaction between BAD and 14-3-3beta was reduced markedly upon a 4 h treatment with 40 microM DATS in both cell lines. Consistent with these results, DATS treatment (40 microM, 4 h) promoted mitochondrial translocation of BAD as revealed by immunocytochemistry. Ectopic expression of constitutively active Akt conferred statistically significant protection against DATS-induced apoptosis. The DATS-induced apoptosis in both cell lines was significantly attenuated in the presence of pan caspase inhibitor zVAD-fmk and caspase 9 specific inhibitor zLEHD-fmk. In conclusion, the present study demonstrates that DATS-induced apoptosis in human prostate cancer cells is mediated, at least in part, by inactivation of Akt signaling axis.
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PMID:Diallyl trisulfide, a constituent of processed garlic, inactivates Akt to trigger mitochondrial translocation of BAD and caspase-mediated apoptosis in human prostate cancer cells. 1616 30

There is an evidence that components of the insulin-like growth factor (IGF)-signaling pathway are involved in the development and progression of prostate cancer. The aim of the present study was to provide a comprehensive analysis of the expression levels of proteins of the IGF axis in prostate cancer. We studied expression of the ligands IGF-I and IGF-II, the inhibitory IGF binding protein-3, the type I IGF receptor (IGF-IR), and the downstream mediator insulin receptor substrate-1 by immunohistochemistry in 56 tissue specimens (28 low-grade and 28 high-grade prostate adenocarcinomas). Protein expression in tumor areas, prostatic intraepithelial neoplasias (PINs), and adjacent benign prostatic tissue were evaluated regarding staining intensity and fraction of positive cells. An immunoreactivity score was established from staining intensity and fraction of positive cells, and correlated with the prognostic clinicopathologic parameters prostate-specific antigen serum levels, Gleason score, and TNM stage. The expression levels of all proteins investigated, except IGF binding protein-3, were up-regulated in PIN and in cancer. IGF-I and IGF-II expression showed a higher expression in high-grade compared with low-grade tumor areas. IGF-I and IGF-II and insulin receptor substrate-1 immunoreactivity was higher in tumors from patients with preoperative prostate-specific antigen serum levels 10 ng/mL or greater, and IGF-II expression was correlated with Gleason score. The data indicate significant alterations in the IGF system as prostate cancer develops. Differential expression of growth-stimulating components of the IGF system may be associated with the malignant phenotype and more aggressive tumor behavior. Expression of IGFs, especially IGF-II, may be predictors of the outcome of prostate cancer.
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PMID:Up-regulation of insulin-like growth factor axis components in human primary prostate cancer correlates with tumor grade. 1626 Feb 72

The need to develop more effective therapies for lung cancer has led to investigations in understanding the molecular mechanisms of the differentiation process, in particular neuroendocrine (NE) differentiation. Recent studies have demonstrated that NE differentiation in non-small cell lung carcinoma (NSCLC) is not uncommon. Those NSCLCs with NE differentiation are considered a form of in transition NE carcinoma and show a more aggressive clinical course compared with NSCLC without NE differentiation. 25.1, a novel protein interacting with mac25/insulin-like growth factor-binding protein-related protein 1 (mac25/IGFBP-rP1), induced NE-like differentiation when collectively overexpressed in M12 prostate cancer cells. We have examined mac25/IGFBP-rP1 and 25.1 as potential molecular regulators in vitro of the NE-differentiation process in lung cancer. In a panel of SCLC and NSCLC cell lines, mac25/IGFBP-rP1 and 25.1 were expressed at higher levels in SCLC. An increase and sustained activation of adenosine 3',5'-cyclic monophosphate (cAMP) levels induced NE-like differentiation in NSCLC cell lines, and a concomitant increase in the expression of mac25/IGFBP-rP1 and 25.1 was observed during the cAMP-regulated differentiation of NCI-H157 cells, suggesting the involvement of these proteins. Furthermore, the collective overexpression of mac25/IGFBP-rP1 and 25.1 in NSCLC cells induced NE-like differentiation as early as 6 h postinfection. The present data suggest that mac25/IGFBP-rP1 and 25.1 may play a functional role in the NE differentiation of NSCLC cell lines and may provide a novel therapeutic target for treating lung cancers, in particular NSCLC with NE differentiation.
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PMID:Neuroendocrine-like differentiation of non-small cell lung carcinoma cells: regulation by cAMP and the interaction of mac25/IGFBP-rP1 and 25.1. 1630 2

Most cases of breast and prostate cancer are not associated with mutations in known high-penetrance genes, indicating the involvement of multiple low-penetrance risk alleles. Studies that have attempted to identify these genes have met with limited success. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium--a pooled analysis of multiple large cohort studies with a total of more than 5,000 cases of breast cancer and 8,000 cases of prostate cancer--was therefore initiated. The goal of this consortium is to characterize variations in approximately 50 genes that mediate two pathways that are associated with these cancers--the steroid-hormone metabolism pathway and the insulin-like growth factor signalling pathway--and to associate these variations with cancer risk.
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PMID:A candidate gene approach to searching for low-penetrance breast and prostate cancer genes. 1634 Oct 85


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