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)

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

LNCaP prostatic cancer cells are characterized by having a PTEN mutation, low levels of type 1 insulin-like growth factor receptor (IGF-IR) and no IRS-1, one of the major substrates of the IGF-IR. The absence of IRS-1, an activator of PI3-kinase, is compensated in these cells by the mutation in PTEN, an inhibitor of PI3-kinase. However, IGF-IR signaling in the absence of IRS-1 can cause cell differentiation and growth arrest. We hypothesized that these three characteristics may not be unrelated, specifically that, together, they may favor the metastatic spread of prostatic cancer cells without decreasing their growth potential. In support of this hypothesis, we report here that: (1) IRS-1 expression increases cell adhesion and decreases cell motility; (2) over-expression of the IGF-IR, in the absence of IRS-1, causes growth arrest and (3) a combination of IGF-IR and IRS-1 restores the transformed phenotype of LNCaP cells. These findings suggest a mechanism by which prostatic cancer cells can achieve metastatic potential without interfering with their growth potential. Oncogene (2000).
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PMID:IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation. 1085 Oct 68

Silibinin, a naturally occurring flavonoid antioxidant found in the milk thistle, has recently been shown to have potent antiproliferative effects against various malignant cell lines, but the underlying mechanism of action remains to be elucidated. We investigated the effect of silibinin on androgen-independent prostate cancer PC-3 cells. At pharmacologically achievable silibinin concentrations (0.02-20 microM), we observed increased insulin-like growth factor-binding protein 3 (IGFBP-3) accumulation in PC-3 cell conditioned medium and a dose-dependent increase of IGFBP-3 mRNA abundance with a 9-fold increase over baseline at 20 microM silibinin. An IGFBP-3 antisense oligodeoxynucleotide that attenuated silibinin-induced IGFBP-3 gene expression and protein accumulation reduced the antiproliferative action of silibinin. We also observed that silibinin reduced insulin receptor substrate 1 tyrosine phosphorylation, indicating an inhibitory effect on the insulin-like growth factor I receptor-mediated signaling pathway. These results suggest a novel mechanism by which silibinin acts as an antiproliferative agent and justify further work to investigate potential use of this compound or its derivatives in prostate cancer treatment and prevention.
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PMID:Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. 1105 49

LNCaP cells are human prostatic cancer cells that have a frame-shift mutation of the tumor suppressor gene PTEN and do not express the insulin receptor substrate-1 (IRS-1), a major substrate of the type 1 insulin-like growth factor receptor (IGF-IR). Ectopic expression of IRS-1 in LNCaP cells increases cell adhesion and decreases cell motility by an IGF-I-independent mechanism. We show now that these effects of IRS-1 are accompanied by serine phosphorylation of IRS-1 and are inhibited by inhibitors of phosphatidylinositol 3-kinase (PI3K). We have confirmed the requirement for PI3K activity and serine phosphorylation by the use of IRS-1 mutants, expressed in LNCaP cells. Serine phosphorylation inhibits IGF-I-induced tyrosyl phosphorylation of IRS-1, which is restored by the expression of wild-type PTEN or by inhibition of PI3K activity. Finally, IRS-1 in LNCaP cells co-immunoprecipitates with integrin alpha 5 beta 1, and the association is again IGF-I-independent. We conclude that in LNCaP cells, IRS-1 is serine phosphorylated by PI3K, generating effects that are different, and even opposite, from those generated by IGF-I.
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PMID:Mechanisms of regulation of cell adhesion and motility by insulin receptor substrate-1 in prostate cancer cells. 1131 80

The type 1 insulin-like growth factor receptor (IGF1R) mediates tumor cell growth, adhesion, and protection from apoptosis. High plasma IGF-I levels predispose to prostate cancer, but there is no consensus regarding IGF1R expression in primary and metastatic prostate cancer. Recent studies in a human cell line and a mouse model suggest that metastatic prostate cancer cell detachment may be favored by impairing cadherin function via loss of expression of insulin receptor substrate-1 (IRS-1), the principal IGF1R docking molecule. This may be accompanied by PTEN mutation, reactivating a key antiapoptotic pathway, and by IGF1R down-regulation to prevent Shc-mediated differentiation. We studied IGF1R expression in 54 samples of primary prostate tissue including 44 archival and 10 prospectively collected biopsies. We performed semiquantitative immunostaining for the IGF1R, IRS-1, and PTEN, and in situ hybridization for IGF1R. The IGF1R was significantly up-regulated at the protein and mRNA level in primary prostate cancer compared with benign prostatic epithelium. There was a trend toward increased expression of IRS-1 in the malignant biopsies. We also measured IGF1R, IRS-1, and PTEN expression in 12 paired biopsies of primary prostate cancer and subsequent bone metastases. In four cases, IGF1R and IRS-1 levels were lower in the metastases than in the primary tumors. Three of these metastases also lacked significant PTEN staining, compatible with findings in the model systems described above. However, this pattern was relatively uncommon, and 8 of 12 cases expressed detectable IGF1R and IRS-1 in both primary and metastatic biopsies. These findings challenge earlier reports of IGF1R down-regulation in metastatic disease and reinforce the importance of the IGF1R in prostate cancer biology.
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PMID:Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. 1201 76

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

Epidemiological studies suggest that increased intake of fruits and vegetables may be associated with a reduced risk of prostate cancer. Apigenin (4', 5, 7,-trihydroxyflavone), a common dietary flavonoid abundantly present in fruits and vegetables, has shown remarkable anti-proliferative effects against various malignant cell lines. However, the mechanisms underlying these effects remain to be elucidated. We investigated the in vivo growth inhibitory effects of apigenin on androgen-sensitive human prostate carcinoma 22Rv1 tumor xenograft subcutaneously implanted in athymic male nude mice. Apigenin was administered to mice by gavage at doses of 20 and 50 mug/mouse/day in 0.2 ml of a vehicle containing 0.5% methyl cellulose and 0.025% Tween 20 in two different protocols. In the first protocol, apigenin was administered for 2 wk before inoculation of tumor and was continued for 8 wk, resulting in significant inhibition of tumor volume by 44 and 59% (P<0.002 and 0.0001), and wet weight of tumor by 41 and 53% (P<0.05), respectively. In the second protocol, administration of apigenin began 2 wk after tumor inoculation and continued for 8 wk; tumor volume and wet weights of tumor were reduced by 39 and 53% (P<0.01 and 0.002) and 31 and 42% (P<0.05), respectively. The tumor inhibitory effect of apigenin was more pronounced in the first protocol of extended treatment, which was associated with increased accumulation of human IGFBP-3 in mouse serum along with significant increase in IGFBP-3 mRNA and protein expression in tumor xenograft. Apigenin intake by these mice also resulted in simultaneous decrease in serum IGF-I levels and induction of apoptosis in tumor xenograft. Importantly, tumor growth inhibition, induction of apoptosis, and accumulation of IGFBP-3 correlated with increasing serum and tumor apigenin levels. In both studies, animals did not exhibit any signs of toxicity or reduced food consumption. In cell culture studies, apigenin treatment resulted in cell growth inhibition and induction of apoptosis, which correlated with increased accumulation of IGFBP-3 in culture medium and cell lysate. These effects were associated with significant reduction in IGF-I secretion; inhibition of IGF-I-induced cell cycle progression and insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, along with an increase in sub-G1 peak by apigenin. Further, treatment of cells with IGFBP-3 antisense oligonucleotide reversed these effects and attenuated apigenin-mediated inhibition of IRS-1 phosphorylation conferring inhibitory effects of apigenin on IGF-signaling. This study presents the first evidence that the in vitro and in vivo growth inhibitory effects of apigenin involve modulation of IGF-axis signaling in prostate cancer.
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PMID:Up-regulation of insulin-like growth factor binding protein-3 by apigenin leads to growth inhibition and apoptosis of 22Rv1 xenograft in athymic nude mice. 1623 Mar 33

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 hedgehog signalling inhibitor cyclopamine has been shown to induce growth inhibition and cell cycle arrest in prostate cancer cell lines, but the mechanism of action has not been clearly defined, and observations between laboratories have not always been consistent. We first observed that albumin can protect PC-3 prostate cancer cells from cyclopamine-induced growth inhibition, suggesting that cyclopamine binds to albumin, and that only free cyclopamine is active. We then conducted a phospho-site protein kinase screen to elucidate the mechanism of cyclopamine-induced growth inhibition. Treatment of PC-3 cells with 5 or 10 microM cyclopamine for 72h resulted in a decrease in cell viability of approximately 50% and approximately 75%, respectively. A phospho-site protein kinase screen showed that cyclopamine decreased levels of phospho-Thr(187)-p27 by 71%. This phospho-site on p27 positively regulates its ubiquitin degradation; therefore a decrease in phospho-Thr(187)-p27 should correlate with increased levels of p27. Consistent with this hypothesis, treatment of PC-3 cells with cyclopamine resulted in a approximately 3-fold increase in p27 protein levels. Cdk-2 phosphorylates Thr(187)-p27, and immunoblotting demonstrated that cyclopamine treatment of PC-3 cells reduces the expression of cdk-2. Furthermore, cyclopamine decreased the levels of phosphorylated (activated) Akt, which is known to increase p27 degradation via Skp-2-induced ubiquitination. The mechanism by which cyclopamine decreases phosphorylated Akt is currently under investigation, but it may involve our observed cyclopamine-induced reduction in IRS-1 and IGF-II expression. These results demonstrate novel molecular correlates of cyclopamine-induced growth inhibition of prostate cancer cells.
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PMID:The hedgehog pathway inhibitor cyclopamine increases levels of p27, and decreases both expression of IGF-II and activation of Akt in PC-3 prostate cancer cells. 1760 33

Proper activation of phosphoinositide 3-kinase-Akt pathway is critical for the prevention of tumorigenesis. Recent data have characterized a negative feedback loop, wherein mammalian target of rapamycin (mTOR) blocks additional activation of the Akt/mTOR pathway through inhibition insulin receptor substrate 1 (IRS-1) function. However, the potential of IRS-1 inhibition during rapamycin treatment has not been examined. Herein, we show that IRS-1 antisense oligonucleotide and rapamycin synergistically antagonize the activation of mTOR in vivo and induced tumor suppression, through inhibition of proliferation and induction of apoptosis, in prostate cancer cell xenografts. These data demonstrate that the addition of agents that blocks IRS-1 potentiate the effect of mTOR inhibition in the growth of prostate cancer cell xenografts.
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PMID:Antineoplastic effect of rapamycin is potentiated by inhibition of IRS-1 signaling in prostate cancer cells xenografts. 1826 22

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