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)

The differential expression of genes and related proteins of multidrug resistance in chemoresistant prostate cancer cell lines were elucidated in this study. RNA extracted from doxorubicin-resistant rat prostate cancer (PCa) cells (AT3/ADR1000) and native PCa cells was hybridized to expression arrays containing cDNAs from 588 known genes. Differential expression of selected genes was confirmed by quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis. Protein contents were measured by fluorescent flow cytometry and immunoblotting. Localization of selected proteins in cells was observed by immunocytochemical staining. Up-regulation of eleven genes and down-regulation of one single gene were displayed in the chemoresistant prostate cancer cells. Overexpression of mRNAs in macrophage migration inhibitory factor (MIF), DNA binding protein inhibitor 1 (ID1), and glutathione S-transferase-pi (GST-pi) were confirmed by gene-specific RT-PCR. Protein over-expression of GST-pi, MIF, and ID1 in resistant cells were 3.3-, 1.5-, and 1.5-fold to native cells, respectively. Immunocytochemistry revealed that GST-pi, MIF, and ID1 were present primarily in the cytoplasm of tumor cells, but ID1 also could be found in the nucleus. AT3/ADR1000 drug-resistant PCa cells displayed significantly increased expression of GST-pi, MIF, and ID1 proteins when compared with native PCa cells. It indicates these genes may play a role in drug resistance of prostate cancer.
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PMID:Increasing expression of GST-pi MIF, and ID1 genes in chemoresistant prostate cancer cells. 1672 43

Consumption of lycopene, a carotenoid without provitamin A activity, has been associated with a lower risk of prostate and breast cancer. Lutein is another carotenoid that may be associated with a reduced risk of age-related macular degeneration, the leading cause of blindness in adults 65 years of age and older. Bioactive compounds such as lycopene and lutein, derived from natural plant sources, have been shown to act at low substrate levels through the action of intrinsic cytokines and growth factors and their receptors within tissues, particularly those of the fibroblast growth factor and transforming growth factor beta families. The effects of grapefruit-derived and commercial lycopene and lutein preparations on androgen independent cultured malignant type II tumor cells [Dunning R3327AT3 or AT3 cells (androgen-responsive, slow-growing tumor cells with well developed epithelium and stroma)] were compared to their benign parent type I tumor epithelial cells (DTE). Results demonstrated that both lycopene, in an alpha -cyclodextrin water soluble carrier, and lutein inhibited malignant AT3 cells in a concentration and time-dependent manner. No such effect was observed when benign DTE cells were examined, demonstrating selective inhibition of extremely malignant AT3 prostate cancer cells relative to their benign parent. Lutein demonstrated a similar but slightly diminished response as lycopene. When cells were treated with cocktails of lycopene and lutein, no synergistic or additive effect occurred. These studies are consistent with epidemiological studies that show inverse relationships of these carotenoids with prostate cancer.
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PMID:Lycopene and lutein inhibit proliferation in rat prostate carcinoma cells. 1764 Jan 63

Using alternative splicing reporters we have previously observed mesenchymal epithelial transitions in Dunning AT3 rat prostate tumors. We demonstrate here that the Dunning DT and AT3 cells, which express epithelial and mesenchymal markers, respectively, represent an excellent model to study epithelial transitions since these cells recapitulate gene expression profiles observed during human prostate cancer progression. In this manuscript we also present the development of two new tools to study the epithelial transitions by imaging alternative splicing decisions: a bichromatic fluorescence reporter to evaluate epithelial transitions in culture and in vivo, and a luciferase reporter to visualize the distribution of mesenchymal epithelial transitions in vivo.
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PMID:Dunning rat prostate adenocarcinomas and alternative splicing reporters: powerful tools to study epithelial plasticity in prostate tumors in vivo. 1852 50

Calreticulin is an essential, multifunctional Ca(2+)-binding protein that participates in the regulation of intracellular Ca(2+) homeostasis, cell adhesion, and chaperoning. Calreticulin is abundantly expressed and regulated by androgens in prostate epithelial cells. Given the importance of both calreticulin in multiple essential cellular activities and androgens in prostate cancer, we investigated the possibility of a role for calreticulin in prostate cancer progression. Immunohistochemistry revealed the down-regulation of calreticulin in a subset of human prostate cancer specimens. Prostate cancer cells overexpressing exogenous calreticulin produced fewer colonies in both monolayer culture and soft agar. Furthermore, calreticulin overexpression also inhibited tumor growth in the orthotopic PC3 xenograft tumor model and macroscopic lung metastasis in the rat Dunning AT3.1 prostate tumor model. To address the potential mechanism of calreticulin suppression of prostate cancer, we generated calreticulin mutants with different functional domains deleted. The calreticulin mutants containing the P-domain, which binds to other endoplasmic reticulum chaperone proteins, were sufficient for the suppression of PC3 growth in colony formation assays. Overall, our data support the hypothesis that calreticulin inhibits growth and/or metastasis of prostate cancer cells and that this suppression requires the P-domain.
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PMID:Suppressive roles of calreticulin in prostate cancer growth and metastasis. 1960 64

Metastatic dissemination in prostate cancer is often early, but not all cancer cells form clinical metastases. Map kinase kinase 4 (MKK4) suppresses metastasis in a preclinical prostate cancer model. We hypothesize that MKK4 will specifically inhibit metastatic colonization through impaired proliferation. Three highly metastatic rat prostate cancer cell lines (AT6.1, Mat-Lu and AT3.1) were employed. Stably over-expressing HA-MKK4 or vector control lines were injected into immunocompromised mice. These experiments validated that HA-MKK4 specifically affects metastatic colonization and increases survival. Median survival (days) with HA-MKK4 vs. vector was 42 vs. 28 (p < 0.0001) for AT6.1, 25 vs. 19 (p < 0.0001) for Mat-Lu and 27 vs. 20 (p < 0.0001) for AT3.1. HA-MKK4 suppresses colonization within 14 days post dissemination, after which exponential proliferation resumes. Although overt metastases retain HA-MKK4, it is inactive within these lesions. Nonetheless, metastasis-derived cell lines were shown to retain functional HA-MKK4 and like their parental HA-MKK4 line are suppressed for experimental metastasis formation in vivo. Disseminated AT6.1-HA-MKK4 cells were analyzed and were found to have an alteration in cell cycle. Specifically, there was an accumulation of cells in G1-phase (p = 0.024) and decrease in S-phase (p = 0.037) compared with vector. In multiple prostate cancer lines, HA-MKK4 suppresses an early step in metastatic colonization. These data support a model in which MKK4 activation at the metastatic site causes a cell-cycle arrest, which is eventually overcome despite presence of functional HA-MKK4. Further studies will specifically interrogate the regulation of MKK4 activation within the metastatic microenvironment and the down-stream molecular events critical for metastasis suppression.
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PMID:MKK4 suppresses metastatic colonization by multiple highly metastatic prostate cancer cell lines through a transient impairment in cell cycle progression. 2135 Oct 92

Hormonal therapies, mainly combinations of anti-androgens and androgen deprivation, have been the mainstay treatment for advanced prostate cancer because the androgen-androgen receptor (AR) system plays a pivotal role in the development and progression of prostate cancers. However, the emergence of androgen resistance, largely due to inefficient anti-hormone action, limits the therapeutic usefulness of these therapies. Here, we report that 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl)nicotinamide (DIMN) acts as a novel anti-androgenic compound that may be effective in the treatment of both androgen-dependent and androgen-independent prostate cancers. Through AR structure-based virtual screening using the FlexX docking model, fifty-four compounds were selected and further screened for AR antagonism via cell-based tests. One compound, DIMN, showed an antagonistic effect specific to AR with comparable potency to that of the classical AR antagonists, hydroxyflutamide and bicalutamide. Consistent with their anti-androgenic activity, DIMN inhibited the growth of androgen-dependent LNCaP prostate cancer cells. Interestingly, the compound also suppressed the growth of androgen-independent C4-2 and CWR22rv prostate cancer cells, which express a functional AR, but did not suppress the growth of the AR-negative prostate cancer cells PPC-1, DU145, and R3327-AT3.1. Taken together, the results suggest that the synthetic compound DIMN is a novel anti-androgen and strong candidate for useful therapeutic agent against early stage to advanced prostate cancer.
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PMID:Structure-based virtual screening and identification of a novel androgen receptor antagonist. 2279 67


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