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)

Hypothalamic growth hormone-releasing hormone (GHRH) controls the release of growth hormone and acts as a growth factor in various tumors. Potent antagonistic analogues of GHRH have been synthesized that strongly suppress the growth of diverse cancers through several mechanisms. However, the influence of GHRH antagonists on the redox (reduction/oxidation) status of cancers has not been investigated. Cellular generation of reactive oxygen species (ROS) is central to redox signaling and is implicated in the initiation, development, and progression of cancer. In this study, we evaluated by Western blot the effects in vitro of GHRH and its antagonist JMR-132 on proliferating cell nuclear antigen, tumor suppressor protein p53, transcription factor NF-kappaB p50 and its phosphorylated form, caspase 3, and cleaved caspase 3 in the LNCaP human prostate cancer cell line. GHRH stimulated and GHRH antagonist inhibited the expression of the major antioxidant enzymes, as well as the expression of COX 2 and cytochrome c oxidase IV, which are enzymes involved in the generation of ROS. GHRH augmented and GHRH antagonist suppressed lipid and protein oxidative stress markers, as well as the intracellular generation of ROS. In all these tests, GHRH antagonists exerted strong antioxidant activity. Because the metabolism of ROS and oxidative stress have been associated with initiation and progression of not only prostate tumors but also other malignancies, our findings reinforce previous experimental evidence that GHRH antagonists could be useful for cancer therapy.
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PMID:Antioxidant activity of growth hormone-releasing hormone antagonists in LNCaP human prostate cancer line. 1907 33

The Clusterin (CLU) gene produces different forms of protein products, which vary in their biological properties and distribution within the cell. Both the extra- and intracellular CLU forms regulate cell proliferation and apoptosis. Dis-regulation of CLU expression occurs in many cancer types, including prostate cancer. The role that CLU plays in tumorigenesis is still unclear. We found that CLU over-expression inhibited cell proliferation and induced apoptosis in prostate cancer cells. Here we show that depletion of CLU affects the growth of PC-3 prostate cancer cells. Following siRNA targeting all CLU mRNA variants, all protein products quickly disappeared, inducing cell cycle progression and higher expression of specific proliferation markers (i.e., H3 mRNA, PCNA, and cyclins A, B1, and D) as detected by RT-qPCR and Western blot. Quite surprisingly, we also found that the turnover of CLU protein is very rapid and tightly regulated by ubiquitin-proteasome mediated degradation. Inhibition of protein synthesis by cycloheximide showed that CLU half-life is less than 2 h. CLU protein products were found poly-ubiquitinated by co-immuniprecipitation. Proteasome inhibition by MG132 caused stabilization and accumulation of all CLU protein products, including the nuclear form of CLU (nCLU), and committing cells to caspase-dependent death. In conclusion, proteasome inhibition may induce prostate cancer cell death through accumulation of nCLU, a potential tumor suppressor factor.
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PMID:Clusterin is a short half-life, poly-ubiquitinated protein, which controls the fate of prostate cancer cells. 1913 41

We have reported that a 10-herbal traditional formula containing Korean Angelica gigas Nakai (AGN) exerts potent anti-cancer efficacy and identified decursin and decursinol angelate (DA) from AGN as novel anti-androgens. Here, we determined whether AGN would exert in vivo anti-cancer activity and whether decursin or DA could account for its efficacy. The AGN ethanol extract was tested against the growth of mouse Lewis lung cancer (LLC) allograft in syngenic mice or human PC-3 and DU145 prostate cancer xenograft in immunodeficient mice. The pharmacokinetics of decursin and DA were determined. The AGN extract significantly inhibited LLC allograft growth (30 mg/kg) and PC-3 and DU145 xenograft growth (100 mg/kg) without affecting the body weight of the host mice. Biomarker analyses revealed decreased cell proliferation (Ki67, PCNA), decreased angiogenesis (VEGF, microvessel density) and increased apoptosis (TUNEL, cPARP) in treated tumors. Decursin and DA injected intraperitoneally were rapidly hydrolyzed to decursinol. Decursinol and decursin at 50 mg/kg inhibited LLC allograft growth to the same extent, comparable to 30 mg AGN/kg. Therefore the AGN extract possessed significant in vivo anti-cancer activity, but decursin and DA only contributed moderately to that activity, most likely through decursinol.
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PMID:In vivo anti-cancer activity of Korean Angelica gigas and its major pyranocoumarin decursin. 1922 17

Radiotherapy (RT) is a common treatment for localised prostate cancer, but can cause important side effects. The therapeutic efficacy of RT can be enhanced by pharmacological compounds that target specific pathways involved in cell survival. This would elicit a similar therapeutic response using lower doses of RT and, in turn, reducing side effects. This study describes the antitumour activity of the novel Akt inhibitor 8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one (Palomid 529 or P529) as well as its ability to decrease radiation-activated phospho-Akt (p-Akt) signalling in a prostate cancer model. P529 showed a potent antiproliferative activity in the NCI-60 cell lines panel, with growth inhibitory 50 (GI50) <35 microM. In addition, P529 significantly enhanced the antiproliferative effect of radiation in prostate cancer cells (PC-3). Analysis of signalling pathways targeted by P529 exhibited a decrease in p-Akt, VEGF, MMP-2, MMP-9, and Id-1 levels after radiation treatment. Moreover, the Bcl-2/Bax ratio was also reduced. Treatment of PC-3 tumour-bearing mice with 20 mg kg(-1) P529 or 6 Gy radiation dose decreased tumour size by 42.9 and 53%, respectively. Combination of both treatments resulted in 77.4% tumour shrinkage. Decreased tumour growth was due to reduced proliferation and increased apoptosis (as assessed by PCNA and caspase-3 immunostaining). Our results show the antitumour efficacy of P529 alone, and as a radiosensitiser, and suggest that this compound could be used in the future to treat human prostate cancer.
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PMID:The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer. 1924 Jul 17

We have previously shown that administration of a combination of micronutrients (selenium, vitamin E, and lycopene) inhibits prostate cancer (PCa) development in the Lady transgenic model. In the present study, we examine timing of initiation of micronutrients, and the effect of micronutrient combinations, on PCa development in Lady transgenic model. Transgenic males were randomized to either a control diet; control diet supplemented with human equivalent doses of vitamin E, selenium, and lycopene (E+S+L); or control diet supplemented with vitamin E and selenium (E+S). In separate experiments, the combination of E+S+L was initiated at varying time points (4, 8, 20, and 36 weeks of age). A combination of E+S+L resulted in a significant reduction in PCa and liver metastasis when intervention was commenced within 8 weeks of age (P < 0.0001). Immunohistochemical analysis revealed a strong correlation between disease-free state with up-regulation of the prognostic marker p27(Kip1) (P < 0.0001) and decreased expression of proliferating cell nuclear antigen and significantly increased apoptotic index (P < 0.0001). On the contrary, a combination of E+S was not effectual in preventing PCa, with a high proportion (84.6%) of animals developing PCa and a small proportion (11.5%) developing high-grade PIN. Early commencement of micronutrients (E+S+L) is beneficial in reducing PCa. Lycopene is an essential component of the combination and effective (when used with E+S) for PCa prevention. These observations provide support for their chemopreventive effect and some clues about their mechanism of action. These key findings will be complementary to the outcome from the Selenium and Vitamin E Chemoprevention Trial.
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PMID:A combination of micronutrients is beneficial in reducing the incidence of prostate cancer and increasing survival in the Lady transgenic model. 1940 31

Loss of function at the Pten tumor-suppressor locus is a common genetic modification found in human prostate cancer. While recent in vivo and in vitro data support an important role of aberrant ErbB-2 signaling to clinically relevant prostate target genes, such as cyclin D1, the role of Pten in ErbB-2-induced prostate epithelial proliferation is not well understood. In the Pten-deficient prostate cancer cell line, LNCaP, restoration of Pten was able to inhibit ErbB-2- and heregulin-induced cell cycle progression, as well as cyclin D1 protein levels and promoter activity. Previously, we established that probasin-driven ErbB-2 transgenic mice presented with high-grade prostate intraepithelial neoplasia and increased nuclear cyclin D1 levels. We show that mono-allelic loss of pten in the probasin-driven-ErbB-2 model resulted in increased nuclear cyclin D1 and proliferating cell nuclear antigen levels and decreased disease latency compared to either individual genetic model and, unlike the probasin-driven-ErbB-2 mice, progression to adenocarcinoma. Activated 3-phosphoinositide-dependent protein kinase-1 was observed during cancer initiation combined with the activation of p70S6K (phospho-T389) and inactivation of the 4E-binding protein-1 (phosphorylated on T37/46) and was primarily restricted to those cases of prostate cancer that had progressed to adenocarcinoma. Activation of mTOR was not seen. Our data demonstrates that Pten functions downstream of ErbB-2 to restrict prostate epithelial transformation by blocking full activation of the PDK1 signaling cascade.
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PMID:A reduction in Pten tumor suppressor activity promotes ErbB-2-induced mouse prostate adenocarcinoma formation through the activation of signaling cascades downstream of PDK1. 1944 6

The hormonal-regulated serpin, ovine uterine serpin (OvUS), also called uterine milk protein (UTMP), inhibits proliferation of lymphocytes and prostate cancer (PC-3) cells by blocking cell-cycle progression. The present aim was to identify cell-cycle-related genes regulated by OvUS in PC-3 cells using the quantitative human cell-cycle RT(2) Profiler PCR array. Cells were cultured +/-200 microg/ml recombinant OvUS (rOvUS) for 12 and 24 h. At 12 h, rOvUS increased expression of three genes related to cell-cycle checkpoints and arrest (CDKN1A, CDKN2B, and CCNG2). Also, 14 genes were down-regulated including genes involved in progression through S (MCM3, MCM5, PCNA), M (CDC2, CKS2, CCNH, BIRC5, MAD2L1, MAD2L2), G(1) (CDK4, CUL1, CDKN3) and DNA damage checkpoint and repair genes RAD1 and RBPP8. At 24 h, rOvUS decreased expression of 16 genes related to regulation and progression through M (BIRC5, CCNB1, CKS2, CDK5RAP1, CDC20, E2F4, MAD2L2) and G(1) (CDK4, CDKN3, TFDP2), DNA damage checkpoints and repair (RAD17, BRCA1, BCCIP, KPNA2, RAD1). Also, rOvUS down-regulated the cell proliferation marker gene MKI67, which is absent in cells at G(0). Results showed that OvUS blocks cell-cycle progression through upregulation of cell-cycle checkpoint and arrest genes and down-regulation of genes involved in cell-cycle progression.
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PMID:Changes in expression of cell-cycle-related genes in PC-3 prostate cancer cells caused by ovine uterine serpin. 1953 Feb 25

The development of prostate cancer is believed to be a multistep process, progressing sequentially from normal epithelium, to prostatic intraepithelial neoplasia (PIN) and, finally, to invasive neoplasia. Malignant stem cells within the basal cell layer of the prostatic epithelium are believed to play an important role in the failure of androgen-ablation therapy that occurs in the most advanced form of prostate cancer. The aim of the present study was to immunohistochemically characterize the lesions of canine PIN. Prostatic tissue from five dogs with PIN was compared with normal prostate tissue from nine further dogs. There was an increase in the number of basal epithelial cells in lesions consistent with PIN as defined by expression of the nuclear protein p63. These lesions had elevated expression of proliferating cell nuclear antigen (PCNA) and heterogeneous labelling for the nuclear androgen receptor (AR). These findings suggest that the basal cells present in PIN may play a role in canine prostate carcinogenesis and that the proliferation of these cells occurs despite the heterogeneous expression of the AR.
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PMID:Immunohistochemical characterization of canine prostatic intraepithelial neoplasia. 1964 31

Sun ginseng (SG) was recently developed as a heat-processed form of ginseng. The Rg3, Rk1, and Rg5 ginsenosides are its main ginsenoside components. SG has been reported to have more potent pharmacological activities than red ginseng (RG), where these pharmacological activities include vasodilatory, anti-oxidant and anti-tumorigenic effects. In the present study, we investigated KG-135, the ginsenoside-rich fraction of SG and demonstrated that this fraction inhibits proliferation of human prostate cancer cells both in vitro and in vivo. KG-135 caused a significant growth inhibition of DU145 and PC-3 human prostate cancer cells. KG-135 induced cell cycle arrest in the G1 phase and caused an associated increase in the p21(Cip1) protein levels. When KG-135 was fed to mice that had been xenografted with DU145 tumors, a time-dependent inhibition of tumor growth was noted without any observed toxicity. Immunohistochemical analysis of the tumor tissues showed that KG-135 led to a decrease in the expression of proliferating cell nuclear antigen (PCNA). Microarray analysis of the tumors revealed that KG-135 inhibited tumor growth and also caused changes in the expression levels of multiple cancer-related genes. These data suggest that KG-135 effectively inhibits prostate cancer cell proliferation. Its mechanism of action likely involves cyclin inhibition and regulation of the expression of the TNFRSF25 and ADRA2A genes.
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PMID:KG-135, enriched with selected ginsenosides, inhibits the proliferation of human prostate cancer cells in culture and inhibits xenograft growth in athymic mice. 1976 91

Constitutive activation of phosphoinositide 3-kinase (PI3K)-Akt pathway transmits growth-regulatory signals that play a central role in promoting survival, proliferation, and angiogenesis in human prostate cancer cells. Here, we assessed the efficacy of inositol hexaphosphate (IP6) against invasive human prostate cancer PC-3 and C4-2B cells and regulation of PI3K-Akt pathway. IP6 treatment of cells suppressed proliferation, induced apoptosis along with caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage, and inhibited constitutive activation of Akt and its upstream regulators PI3K, phosphoinositide-dependent kinase-1 and integrin-linked kinase-1 (ILK1). Downstream of Akt, IP6 inhibited the phosphorylation of glycogen synthase kinase-3alpha/beta at Ser(21/9) and consequently reduced cyclin D1 expression. Efficacy studies employing PC-3 tumor xenograft growth in nude mice showed that 2% (w/v) IP6 feeding in drinking water inhibits tumor growth and weight by 52% to 59% (P < 0.001). Immunohistochemical analysis of xenografts showed that IP6 significantly reduces the expression of molecules associated with cell survival/proliferation (ILK1, phosphorylated Akt, cyclin D1, and proliferating cell nuclear antigen) and angiogenesis (platelet endothelial cell adhesion molecule-1 or CD31, vascular endothelial growth factor, endothelial nitric oxide synthase, and hypoxia-inducible factor-1alpha) together with an increase in apoptotic markers (cleaved caspase-3 and PARP). These findings suggest that, by targeting the PI3K-ILK1-Akt pathway, IP6 suppresses cell survival, proliferation, and angiogenesis but induces death in prostate cancer cells, which might have translational potential in preventing and controlling the growth of advanced and aggressive prostate cancer for which conventional chemotherapy is not effective.
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PMID:Inositol hexaphosphate suppresses growth and induces apoptosis in prostate carcinoma cells in culture and nude mouse xenograft: PI3K-Akt pathway as potential target. 1992 Jan 84


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