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)

Four transplantable cell lines (PA-I, II, III, and IV) derived from four Lobund-Wistar (L-W) rats that manifested spontaneous prostate cancer have demonstrated metastatic capacity in visceral organs. Interestingly, PA-III cells, when deposited over the scapula or calvarium of the Lobund-Wistar rat, could produce lytic and blastic reactions on rat skeleton. Since growth factors and growth factor receptors have been implicated in bone remodeling, cancer biology, and metastatic growth of cancer cells, we have examined 1) the effects of insulin and insulin-like growth factors (IGF-I and IGF-II) on the proliferation of PA-III cells; and 2) the presence of specific receptors for these peptides. IGF-I (0.5 to 100 ng/ml), IGF-II (0.5 to 100 ng/ml), and insulin (0.5 to 10 micrograms/ml) stimulated tritiated thymidine uptake and increased the number of PA-III cells in culture. Receptor studies demonstrated the presence of specific bindings sites for IGF-I and II but not for insulin. The number and affinity of the receptor sites were: IGF-I (nb = 675 fmol/100 g protein, Kd = 0.56 nmol) and IGF-II (nb = 225 fmol/100 g protein, Kd = 0.71 nmol). Molecular characterization of IGF binding sites by polyacrylamide gel electrophoresis under denaturing conditions indicated only the presence for the type I IGF receptor. The presence of the IGF-I receptor and the absence of IGF-II and insulin receptors are discussed in relation to the capacity of PA-III cells to produce bone lesions on the L-W rat.
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PMID:Mitogenic effects of insulin and insulin-like growth factors on PA-III rat prostate adenocarcinoma cells: characterization of the receptors involved. 166 15

The role of insulin-like growth factor I (IGF-I) in the growth and development of prostate cancer was studied using established human prostate cancer cell lines. Under steroid and growth factor-free culture conditions, IGF-I significantly stimulated the androgen-independent cell lines PC-3 and DU-145 to incorporate [3H]thymidine into DNA, while the androgen-dependent cell line, LNCaP, was not affected. However, in the presence of dihydrotestosterone (DHT), DNA synthesis of LNCaP cells was stimulated by IGF-I in a dose-dependent manner. None of the cell lines tested secreted an immunoreactive level of IGF-I into their conditioned medium. Characterization of receptors by ligand binding assays revealed that all prostate cancer cell lines tested express specific binding sites for IGF-I with similar dissociation constants (0.23-0.39 nM). Crosslinking studies supported the suggestion that 125I-IGF-I was bound to a receptor on these cells. The IGF-I receptor concentrations of androgen-independent cell lines were significantly higher than those of the androgen-dependent cell line. Androgen appeared to affect neither the expression of IGF-I receptors nor the secretion of IGF-I. The results suggest that IGF-I may play an important role in stimulating the growth and progression of prostate cancer.
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PMID:Insulin-like growth factor I: action and receptor characterization in human prostate cancer cell lines. 848 57

We have previously shown that LHRH agonists exert a direct and specific inhibitory action on the proliferation of the androgen-independent DU 145 prostate cancer cell line; however, the cellular mechanisms mediating this antiproliferative action are not well defined. It is well known that the insulin-like growth factor (IGF) system plays a crucial role in the local regulation of the growth of androgen-independent prostate cancer. The present experiments were performed to evaluate whether LHRH agonists might exert their antimitogenic effect by interfering with the activity of the locally expressed IGF system. To this purpose, the effects of the LHRH agonist Zoladex (LHRH-A) on 1) the mitogenic action of IGF-I, 2) the tyrosine phosphorylation of type 1 IGF-I receptor (IGF-IR), 3) the concentration of IGF-IR, and 4) the secretion of IGF-binding protein-3 were studied. The results obtained show that in DU 145 cells, LHRH-A 1) counteracts the mitogenic action of IGF-I in a dose-dependent manner, 2) prevents the IGF-I-induced tyrosine phosphorylation of the IGF-IR, 3) reduces the concentration of IGF-IR without affecting its Kd value, and 4) does not affect the secretion of IGF-binding protein-3 in the conditioned medium from these cells. These data suggest that LHRH agonists may inhibit the proliferation of human androgen-independent prostate tumor cells by interfering with some of the cellular mechanisms mediating the stimulatory action of the IGF system.
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PMID:Luteinizing hormone-releasing hormone agonists interfere with the mitogenic activity of the insulin-like growth factor system in androgen-independent prostate cancer cells. 988 42

Recent studies have shown that high insulin-like growth factor I (IGF-I) blood level is a risk factor in breast and prostate cancer. The aim of this study was to determine whether the mitogenic activity of IGF-I in mammary cancer cells can be reduced by the dietary carotenoid lycopene. The anticancer activity of lycopene, the major tomato carotenoid, has been suggested by in vitro, in vivo, and epidemiological studies. Growth stimulation of MCF7 mammary cancer cells by IGF-I was markedly reduced by physiological concentrations of lycopene. The inhibitory effects of lycopene on MCF7 cell growth were not accompanied by apoptotic or necrotic cell death, as determined by annexin V binding to plasma membrane and propidium iodide staining of nuclei in unfixed cells. Lycopene treatment markedly reduced the IGF-I stimulation of tyrosine phosphorylation of insulin receptor substrate 1 and binding capacity of the AP-1 transcription complex. These effects were not associated with changes in the number or affinity of IGF-I receptors, but with an increase in membrane-associated IGF-binding proteins, which were previously shown in different cancer cells to negatively regulate IGF-I receptor activation. The inhibitory effect of lycopene on IGF signaling was associated with suppression of IGF-stimulated cell cycle progression of serum-starved, synchronized cells. Moreover, in cells synchronized by mimosine treatment, lycopene delayed cell cycle progression after release from the mimosine block. Collectively, the above data suggest that the inhibitory effects of lycopene on MCF7 cell growth are not due to the toxicity of the carotenoid but, rather, to interference in IGF-I receptor signaling and cell cycle progression.
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PMID:Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. 1079 22

Prostate cancer is the most diagnosed invasive malignancy in males. Androgens and oestrogens have been implicated in the pathogenesis of prostate cancer. We report herein that the pure anti-oestrogen ICI 182,780 (ICI) reduces Ki-67 labelling index and IGF-I receptor levels in rat prostate. Increase of IGF-I mRNA and IGF-binding protein 3 (IGFBP-3) accumulation occur without any effect on prostate weight. Finasteride significantly decreases prostate weight and inhibits IGF-I gene expression. IGFBP-3 mRNA, Akt and phospho-Akt are not affected by finasteride. Co-administration of ICI plus finasteride reduces prostate weight by approximately 50% and causes acinar dilation with decreased luminal epithelial cell thickness. The acinar epithelial cells became atrophic and inactive with minimal cytoplasm. We also demonstrate a synergistic effect of ICI and finasteride on induction of IGFBP-3 accumulation and inhibition of Akt phosphorylation. Because the IGF and IGFBP-3 system plays an important role in prostate epithelial cell proliferation, apoptosis and tumour progression, the inhibitory effects of finasteride and ICI on IGF system may contribute to their anti-proliferative activity. These observations support a potential use of ICI in conjunction with finasteride in the prevention and/or treatment of prostate cancer.
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PMID:Co-administration of finasteride and the pure anti-oestrogen ICI 182,780 act synergistically in modulating the IGF system in rat prostate. 1157 95

Tea polyphenols have been proposed as potential chemopreventive agents against prostate cancer, primarily because of their high intake by populations with reduced cancer incidence and their reported ability to inhibit proliferation and increase apoptosis in prostate cancer cells in culture. Insulin-like growth factor-I (IGF-I) has been implicated as a risk factor for the development of prostate cancer by epidemiological studies and has been shown to be causative in animal models. One of the primary signal transduction pathways activated by IGF-I binding to its receptor is the Akt pathway. We determined that phosphorylated Akt levels are very low in serum-starved human normal prostate epithelial cells (PrEC) and Du145 prostate carcinoma cells, and that treatment of these cells with IGF-I results in a rapid and sustained phosphorylation of Akt. Pre-treatment of PrEC and Du145 cells with doses as low as 20 microg/ml of a mixture of black tea polyphenols (BTP) substantially reduced IGF-I-mediated Akt phosphorylation. This effect of BTP appears to be due partially to the reduced autophosphorylation of IGF-I receptor-1 in BTP-treated cells. BTP pre-treatment also decreased downstream effects of Akt activation including phosphorylation of glycerol synthase kinase-3, increased cyclin D1 protein levels and increased DNA synthesis. Our results indicate that polyphenols from black tea inhibit the IGF-I signal transduction pathway, which has been linked to increased prostate cancer incidence in human populations and, therefore, provide further support for the potential of BTP to prevent prostate cancer.
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PMID:Black tea polyphenols inhibit IGF-I-induced signaling through Akt in normal prostate epithelial cells and Du145 prostate carcinoma cells. 1175 45

Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) can stimulate apoptosis and inhibit cell proliferation directly and independently of binding IGFs or indirectly by forming complexes with IGF-I and IGF-II that prevent them from activating the IGF-I receptor to stimulate cell survival and proliferation. To date, IGF-independent actions only have been demonstrated in a limited number of cells that do not synthesize or respond to IGFs. To assess the general importance of IGF-independent mechanisms, we have generated human IGFBP-3 mutants that cannot bind IGF-I or IGF-II by substituting alanine for six residues in the proposed IGF binding site, Ile(56)/Tyr(57)/Arg(75)/Leu(77)/Leu(80)/Leu(81), and expressing the 6m-hIGFBP-3 mutant construct in Chinese hamster ovary cells. Binding of both IGF-I and IGF-II to 6m-hIGFBP-3 was reduced >80-fold. The nonbinding 6m-hIGFBP-3 mutant still was able to inhibit DNA synthesis in a mink lung epithelial cell line in which inhibition by wild-type hIGFBP-3 previously had been shown to be exclusively IGF-independent. 6m-hIGFBP-3 only can act by IGF-independent mechanisms since it is unable to form complexes with the IGFs that inhibit their action. We next compared the ability of wild-type and 6m-hIGFBP-3 to stimulate apoptosis in serum-deprived PC-3 human prostate cancer cells. PC-3 cells are known to synthesize and respond to IGF-II, so that IGFBP-3 could potentially act by either IGF-dependent or IGF-independent mechanisms. In fact, 6m-hIGFBP-3 stimulated PC-3 cell death and stimulated apoptosis-induced DNA fragmentation to the same extent and with the same concentration dependence as wild-type hIGFBP-3. These results indicate that IGF-independent mechanisms are major contributors to IGFBP-3-induced apoptosis in PC-3 cells and may play a wider role in the antiproliferative and antitumorigenic actions of IGFBP-3.
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PMID:Insulin-like growth factor (IGF)-binding protein-3 mutants that do not bind IGF-I or IGF-II stimulate apoptosis in human prostate cancer cells. 1178 19

Previous studies showed that serum from men consuming a low fat diet and undergoing exercise intervention (DE) reduced LNCaP cell growth and induced apoptosis in vitro. DE also decreased serum IGF-I and increased serum IGF binding protein-1 (IGFBP-1). The present study evaluates the effects of IGF-I and IGFBP-1 on growth and apoptosis of prostate cancer cells in vitro. When IGF-I was added to the post-DE serum, the reduction in LNCaP cell growth and the induction of apoptosis in medium containing post-DE serum alone were reversed. When IGFBP-1 was added to the pre-DE serum samples, LNCaP cell growth was reduced, and apoptosis was induced. IGF-I, long-R(3)-IGF-I (only binds IGF-I receptor), AL(31)Leu(60)-IGF-I (only binds IGFBPs), antihuman IGF-I receptor antibodies, and IGFBP-1 were then added to LNCaP cultures to determine the independent effects of IGF-I and IGFBP-1 on cell growth. Collectively, the results using these agents show that IGF-I and IGFBP-1 exert opposing effects on LNCaP cell growth and apoptosis, and IGFBP-1 acts mainly through an IGF-dependent mechanism. DE results in a decrease in serum IGF-I with increased IGFBP-1 in vivo that is associated with apoptosis and reduced LNCaP and LAPC-4 prostate cancer cell growth in vitro.
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PMID:Insulin-like growth factor I (IGF-I) and IGF binding protein-1 modulate prostate cancer cell growth and apoptosis: possible mediators for the effects of diet and exercise on cancer cell survival. 1274 92

We examined the ability of polyphenols from tomatoes and soy (genistein, quercetin, kaempferol, biochanin A, daidzein and rutin) to modulate insulin-like growth factor-I (IGF-I)-induced in vitro proliferation and apoptotic resistance in the AT6.3 rat prostate cancer cell line. IGF-I at 50 micro g/L in serum-free medium produced maximum proliferation and minimized apoptosis. Polyphenols exhibited different abilities to modulate IGF-I-induced proliferation, cell cycle progression (flow cytometry) and apoptosis (Annexin V/propidium iodide and terminal deoxynucleotidyltransferase-mediated deoxyuridine 5'-triphosphate nick end labeling). Genistein, quercetin, kaempferol and biochanin A exhibited dose-dependent inhibition of growth with a 50% inhibitory concentration (IC(50)) between 25 and 40 micro mol/L, whereas rutin and daidzein were less potent with an IC(50) of >60 micro mol/L. Genistein and kaempferol potently induced G(2)/M cell cycle arrest. Genistein, quercetin, kaempferol and biochanin A, but not daidzein and rutin, counteracted the antiapoptotic effects of IGF-I. Human prostate epithelial cells grown in growth factor-supplemented medium were also sensitive to growth inhibition by polyphenols. Genistein, biochanin A, quercetin and kaempferol reduced the insulin receptor substrate-1 (IRS-1) content of AT6.3 cells and prevented the down-regulation of IGF-I receptor beta in response to IGF-I binding. IGF-I-stimulated proliferation was dependent on activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) and phosphatidylinositide 3-kinase pathways. Western blotting demonstrated that ERK1/2 was constitutively phosphorylated in AT6.3 cells with no change in response to IGF-I, whereas IRS-1 and AKT were rapidly and sensitively phosphorylated after IGF-I stimulation. Several polyphenols suppressed phosphorylation of AKT and ERK1/2, and more potently inhibited IRS-1 tyrosyl phosphorylation after IGF-I exposure. In summary, polyphenols from soy and tomato products may counteract the ability of IGF-I to stimulate proliferation and prevent apoptosis via inhibition of multiple intracellular signaling pathways involving tyrosine kinase activity.
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PMID:Tomato and soy polyphenols reduce insulin-like growth factor-I-stimulated rat prostate cancer cell proliferation and apoptotic resistance in vitro via inhibition of intracellular signaling pathways involving tyrosine kinase. 1284 Feb 8

The IGF system plays an important role in prostate cancer initiation and progression. Most of the biological actions of IGF-I and IGF-II are mediated by activation of the IGF-I receptor (IGF-IR). Evidence accumulated in recent years indicates that acquisition of the malignant phenotype is initially IGF-IR dependent, but progression toward metastatic stages is usually associated with a decrease in IGF-IR levels. The Kruppel-like factor 6 (KLF6) is a zinc finger-containing transcription factor that was shown to be mutated in a significant portion of prostate and other types of cancer. To examine the potential regulation of IGF-IR gene expression by KLF6, we measured KLF6 levels in prostate-derived cell lines displaying different levels of IGF-IR. The results of Western analysis showed that KLF6 levels were higher in nontumorigenic P69 cells expressing high IGF-IR levels than in metastatic M12 cells containing reduced IGF-IR levels. Transient coexpression of wild-type, but not mutated, KLF6 together with an IGF-IR promoter-luciferase reporter plasmid resulted in an approximately 3.4-fold stimulation of IGF-IR promoter activity. Furthermore, KLF6 expression induced a significant increment in endogenous IGF-IR levels. Deletion analysis of the IGF-IR promoter revealed that a cluster of four GC boxes located between nucleotides -399 and -331 mediates a significant portion of the transactivating effect of KLF6. KLF6, although unable to stimulate IGF-IR promoter activity in Sp1-null Drosophila-derived Schneider cells, significantly enhanced the effect of Sp1. To assess the potential interactions between KLF6 and p53 in the regulation of IGF-IR gene expression, transfections were performed in the colorectal cancer cell line HCT116(+/+), which expresses p53, and its HCT116(-/-) derivative, which lacks p53. KLF6 exhibited an enhanced activity in p53-containing, compared with p53-null, cells. In addition, we were able to detect a physical interaction between KLF6 and p53. In summary, we have identified the IGF-IR gene as a novel downstream target for transcription factor KLF6. The regulation of IGF-IR gene expression by KLF6 may have significant implications in terms of cancer initiation and/or progression.
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PMID:Transcriptional activation of the insulin-like growth factor I receptor gene by the Kruppel-like factor 6 (KLF6) tumor suppressor protein: potential interactions between KLF6 and p53. 1513 Oct 18

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