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)

Deficiency in p53-mediated cell death is common in human cancer, contributing to both tumorigenesis and chemoresistance. In an attempt to restore p53, we evaluated in vitro infectivity and cytotoxicity of a wild type (w.t.) p53-expressing adenovirus (Ad-p53) toward a panel of human cancer cell lines (n = 19). At a multiplicity of infection of 30, both Ad-p53 and adenovirus expressing beta-galactosidase (Ad-LacZ) infected greater than 99% of cells derived from brain, lung, breast, ovarian, colon, and prostate cancer, but failed to infect leukemia or lymphoma cells. Ad-p53, but not Ad-LacZ, infection of cancer cells was followed by nuclear accumulation of the CDK inhibitor p21WAFI/CIPI, cell cycle arrest and loss of viability. Ad-p53 induced apoptotic death in cancer cells that express mutant p53, including multi-drug resistant cells, but fewer deaths were observed in some w.t. p53 expressing cells. Ad-p53-infected SKBr3 breast cancer cells were more sensitive to cytotoxicity of the DNA damaging drugs mitomycin C or Adriamycin, but not the M-phase specific drug vincristine. Our results suggest that Ad-p53 is capable of infecting and killing cancer cells of diverse tissue origins (including multi-drug resistant cancer cells), that p21WAFI/CIPI may be a useful marker of p53 infectivity and that there may be synergy between Ad-p53 and either mitomycin C or Adriamycin induced cell death in tumors with p53 mutations.
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PMID:In vitro evaluation of a p53-expressing adenovirus as an anti-cancer drug. 870 13

The molecular mechanism of androgen-independent growth of prostate cancer after androgen ablation was explored in LNCaP cells. An androgen-dependent clonal subline of the LNCaP human prostate carcinoma cell line, LNCaP 104-S, progressed to a slow growing stage (104-R1) and then to a faster growing stage (104-R2) during more than 2 yr of continuous culture in the absence of androgen. Androgen-induced proliferation of 104-S cells is inhibited by the antiandrogen Casodex, while proliferation of 104-R1 and 104-R2 cells is unaffected by Casodex. This indicates that proliferation of 104-R1 and 104-R2 cells is not supported by low levels of androgen in the culture medium. Compared with LNCaP 104-S cells, both 104-R1 and 104-R2 cells express higher basal levels of androgen receptor (AR), and proliferation of these two cell lines is paradoxically repressed by androgen. After continuous passage in androgen-containing medium, 104-R1 cells reverted back to an androgen-dependent phenotype. The mechanism of androgenic repression of 104-R1 and 104-R2 sublines was further evaluated by examining the role of critical regulatory factors involved in the control of cell cycle progression. At concentrations that repressed growth, androgen transiently induced the expression of the cyclin-dependent kinase (cdk) inhibitor p21waf1/cip1 in 104-R1 cells, while expression of the cdk inhibitor p27Kip1 was persistently induced by androgen in both 104-R1 and 104-R2 cells. Induced expression of murine p27Kip1 in 104-R2 cells resulted in G1 arrest. Specific immunoprecipitates of Cdk2 but not Cdk4 from androgen-treated 104-R1 cells contained both p21waf1/cip1 and p27Kip1. This observation was confirmed by in vitro assay of histone H1 and Rb (retinoblastoma protein) phosphorylation by the proteins associated with the immune complex. Furthermore, inhibition of Cdk2 activity correlated with the accumulation of p27Kip1 and not p21waf1/cip1. From these results we conclude that androgenic repression of LNCaP 104-R1 and 104-R2 cell proliferation is due to the induction of p27Kip1, which in turn inhibits Cdk2, a factor critical for cell cycle progression and proliferation.
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PMID:Progression of LNCaP prostate tumor cells during androgen deprivation: hormone-independent growth, repression of proliferation by androgen, and role for p27Kip1 in androgen-induced cell cycle arrest. 965 99

The human prostate cancer (CaP) xenograft, CWR22, mimics human CaP. CWR22 grows in testosterone-stimulated nude mice, regresses after castration, and recurs after 5-6 months in the absence of testicular androgen. Like human CaP that recurs during androgen deprivation therapy, the recurrent CWR22 expresses high levels of androgen receptor (AR). Immunohistochemical, Western, and Northern blot analyses demonstrated that AR expression in the androgen-independent CWR22 is similar to AR expression in the androgen-dependent CWR22 prior to castration. Expression of prostate-specific antigen and human kallikrein-2 mRNAs, two well-characterized androgen-regulated genes in human CaP, was androgen dependent in CWR22. Despite the absence of testicular androgen, prostate-specific antigen and human kallikrein-2 mRNA levels in recurrent CWR22 were higher than the levels in regressing CWR22 tumors from 12-day castrate mice and similar to those in the androgen-stimulated CWR22. Other AR-regulated genes followed a similar pattern of expression. Differential expression screening identified androgen regulation of alpha-enolase and alpha-tubulin as well as other unknown mRNAs. Insulin-like growth factor binding protein-5, the homeobox gene Nkx 3.1, the AR coactivator ARA-70, and cell cycle genes Cdk1 and Cdk2 were androgen regulated in CWR22. In recurrent CWR22, the steady-state levels of all these AR-dependent mRNAs were similar to those in the androgen-stimulated CWR22, despite the absence of testicular androgen. Expression of AR and AR-regulated genes in the androgen-deprived recurrent CWR22 at levels similar to the androgen-stimulated CWR22 suggests that AR is transcriptionally active in recurrent CWR22. Induction of these AR-regulated genes may enhance cellular proliferation in relative androgen absence but through an AR-dependent mechanism. Alternatively, in androgen-independent tumors, induced expression of the AR-regulated gene network might result from a non-AR transcription control mechanism common to these genes.
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PMID:Androgen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes. 986 29

Prostate cancer is the most commonly diagnosed neoplasm in men. LNCaP cells continue to possess many of the molecular characteristics of in situ prostate cancer. These cells lack ras mutations, and mitogen-activated protein kinase (MAPK) is not extensively phosphorylated in these cells. To determine the effects of ras/raf/MAPK pathway activation in these cells, we transfected LNCaP cells with an activatable form of c-raf-1(deltaRaf-1:ER). Activation of deltaRaf-1:ER, with resultant MAPK activation, reduced plating efficiency and soft agarose cloning efficiency 30-fold in LNCaP cells. Cell cycle distribution showed an accumulation of cells in G1 and was associated with the induction of CDK inhibitor p21WAF1/CIP1 at the protein and mRNA levels. p21WAF1/CIP1 mRNA stability was increased after deltaRaf-1:ER activation. In addition, activated deltaRaf-1:ER induced the senescence associated-beta-galactosidase in LNCaP cells. These data demonstrate that raf activation can activate growth inhibitory pathways leading to growth suppression in prostate carcinoma cells and also suggest that raf/MEK/MAPK pathway activation, rather than inhibition, may be a therapeutic target for some human prostate cancer cells.
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PMID:Raf-1-induced cell cycle arrest in LNCaP human prostate cancer cells. 1002 6

Differential gene expression between the androgen sensitive human prostate cancer cell line LNCaP and an insensitive clonal variant, LNCaP-r, was demonstrated by suppression subtractive hybridization. Twenty-one sequences were identified of which 9 are homologous to known genes, 11 are represented by expressed sequence tags (ESTs), and 1 is novel. We present data for 5 of 7 sequences confirmed to be differentially expressed by Northern blot analysis and semiquantitative RT-PCR. Only one gene, fibronectin (FN), was highly overexpressed (>60-fold) in LNCaP-r cells, consistent with previously reported overexpression of FN in prostate cancer. Four sequences were down-regulated in LNCaP-r cells, including an inactive variant of the E2 ubiquitin conjugating enzyme (UEV-1), a novel metalloproteinase-related collagenase (PM5), and a potential tumor suppressor gene (breast basic conserved gene, BBC1). UEV-1 is multifunctional, regulates the cell cycle via cdk1, has homology to MMS2 and likewise functions as a DNA protection protein, and also has homology to TSG101. Aberrant splice variants of TSG101 occur frequently in both breast and prostate cancer, but its mechanism of action is unknown. FN, BBC1, and UEV-1 localize to regions of chromosomal aberration (2q3.4, 16q24.3, and 20q13.2, respectively) associated with advanced prostate cancer and thus may be highly relevant to disease progression.
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PMID:Differentially expressed genes in hormone refractory prostate cancer: association with chromosomal regions involved with genetic aberrations. 1032 86

Low levels of p27Kip1 in primary prostate cancer specimens have been shown to be associated with higher rates of disease recurrence and poor rates of disease-free survival in patients with localized disease. In this study, we provide the first direct evidence showing that dihydrotestosterone (DHT), a major proliferation regulator of prostate cancer, can down-regulate p27Kip1 and stimulate cyclin-dependent kinase-2 (CDK2) activity in established prostate cancer cell lines. We investigated the cooperative effects of DHT and epidermal growth factor (EGF) on the proliferation of androgen-responsive MDA PCa 2a and MDA PCa 2b prostate cancer cells. DHT and EGF each stimulated proliferation of these cells, but exposure of the cells to DHT and EGF together stimulated greater proliferation. Stimulation of cell proliferation by DHT and/or EGF was associated with increased CDK2 activity and a decreased level of p27Kip1. There seems to be a positive feedback stimulation loop between androgen-induced gene transcription and EGF-stimulated signal transduction, as one could stimulate the synthesis of the receptors for the other. Dual blockade of androgen receptor function with the antiandrogen hydroxyflutamide and EGF receptor superfamily-mediated signal transduction with the anti-EGF receptor monoclonal antibody C225 and the anti-HER2 receptor monoclonal antibody Herceptin significantly enhanced growth inhibition of the MDA PCa 2a cells. Our results demonstrate the importance of counteracting both androgen receptors and EGF receptors in the development of novel therapies for prostate cancer.
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PMID:Androgen and epidermal growth factor down-regulate cyclin-dependent kinase inhibitor p27Kip1 and costimulate proliferation of MDA PCa 2a and MDA PCa 2b prostate cancer cells. 1047 2

Accumulating evidence suggests that phosphatases play an important role in regulating a variety of signal transduction pathways that have a bearing on cancer. The kinase-associated phosphatase (KAP) is a human dual-specificity protein phosphatase that was identified as a Cdc2- or Cdk2-interacting protein by a yeast two-hybrid screening, yet the biological significance of these interactions remains elusive. We have identified the KAP gene as an overexpressed gene in breast and prostate cancer by using a phosphatase domain-specific differential-display PCR strategy. Here we report that breast and prostate malignancies are associated with high levels of KAP expression. The sublocalization of KAP is variable. In normal cells, KAP is primarily found in the perinuclear region, but in tumor cells, a significant portion of KAP is found in the cytoplasm. Blocking KAP expression by antisense KAP in a tetracycline-regulatable system results in a reduced population of S-phase cells and reduced Cdk2 kinase activity. Furthermore, lowering KAP expression led to inhibition of the transformed phenotype, with reduced anchorage-independent growth and tumorigenic potential in athymic nude mice. These findings suggest that therapeutic intervention might be aimed at repression of KAP gene overexpression in human breast and prostate cancer.
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PMID:Overexpression of kinase-associated phosphatase (KAP) in breast and prostate cancer and inhibition of the transformed phenotype by antisense KAP expression. 3251 51

The cell cycle is governed by cyclin dependent kinases (cdks), which are activated by binding of cyclins, inhibited by cdk inhibitors and regulated by phosphorylation and dephosphorylation. Exposure to high dose dihydrotestosterone (DHT) inhibits population growth of the human prostate carcinoma cell line, LNCaP. To determine the mechanism of growth arrest by high dose DHT, we assayed the changes in cell cycle profile and the cell cycle regulators that mediate these effects. Treatment of asynchronously growing LNCaP cells with 100 nM DHT caused a G1 arrest. The proportion of cells in S phase fell from 22 to 2%, while the G1 fraction rose from 74 to 92% by 24 h. Loss of phosphorylation of the retinoblastoma protein was noted and cdk4 and cyclin E/ cdk2 activities fell. Inhibition of these G1 cyclin dependent kinases was not due to loss of either cyclin or cdk proteins nor to increases in the cdk inhibitors p16INK4A and p21CiP1. p21Cip1 protein levels remained constant, and cyclin E-associated p21CiP1 fell, suggesting that p21CiP1 is not relevant to this form of cyclin E/cdk2 inhibition. Of note, total p27KiP1 levels and cyclin E-associated p27Kip1 increased as cells arrested and the amount of the CAK activated cdk2 bound to cyclin E decreased. p27KiP1 immunodepletion experiments demonstrated that the DHT-mediated increase in p27Kip1 was sufficient to fully saturate and inhibit target cyclin E/ cdk2. The inhibition of cyclin E/cdk2 by p27Kip1 contributes to G1 arrest of LNCaP following high dose DHT. p27KiP1 may be a key effector of androgen dependent growth modulation in prostate cancer cells.
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PMID:Involvement of p27Kip1 in G1 arrest by high dose 5 alpha-dihydrotestosterone in LNCaP human prostate cancer cells. 1069 12

The mechanism of growth inhibition and triggering of cell death by the antibiotic brefeldin A (BFA) was investigated in human prostatic cancer DU-145 cells. After cells were cultured with various concentrations of BFA, cell number and viability were determined at specified times. Compared with untreated cells, a drastic growth reduction (>80%) with approximately 50% cell death was observed in the cells cultured with BFA (30 ng/mL) for 72 h. Cell-cycle analysis using flow cytometry revealed that such growth inhibition was associated with approximately 85% reduction in the S-phase population, indicating the inhibition of the G(1)-S phase progression. Western blots further showed that cell-cycle-dependent kinases (cdk2 and cdk4), cyclin D(1), and p53 were all downregulated, whereas WAF1 (p21) was upregulated with BFA treatment. Possible induction of apoptosis by BFA was also assessed by TUNEL assay and by DNA analysis using agarose gel electrophoresis. The TUNEL assay demonstrated the positive staining of BFA-treated cells, and gel electrophoresis confirmed nucleosomal DNA ladder formation. Thus, these results suggest that growth inhibition of DU-145 cells by BFA is attributable mainly to a G1 cell-cycle arrest through the modulation of specific cell-cycle regulators. The accompanying cell death may follow a p53-independent apoptotic pathway.
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PMID:Mechanism of Brefeldin A-Induced Growth Inhibition and Cell Death in Human Prostatic Carcinoma Cells. 1085 Dec 91

Epidemiological and clinical data suggest that selenium may prevent prostate cancer, but the biological effects of selenium on normal or malignant prostate cells are not well known. We evaluated the effects of sodium selenite (Na2SeO3) or l-selenomethionine (SeMet) on monolayer and anchorage-independent growth in a series of normal primary prostate cultures (epithelial, stromal, and smooth muscle) and prostate cancer cell lines (LNCaP, PC-3, and DU145). We observed differential, dose-dependent growth inhibition and apoptosis within prostate cancer cells (compared with normal prostate cells) treated with 1-500 microM of Na2SeO3 or SeMet. Na2SeO3 more potently inhibited growth at any given concentration. The androgen-responsive LNCaP cells were the most sensitive to selenium growth suppression (IC50s at 72 h for Na2SeO3 and SeMet were 0.2 and 1.0 microM, respectively). Growth of the primary prostate cells virtually was not suppressed (IC50s at 72 h for Na2SeO3 and SeMet were 22-38 and >500 microM, respectively). We also observed that DNA condensation and DNA fragmentation (terminal deoxynucleotidyltransferase dUTP nick end labeling/fluorescence-activated cell sorting) were elevated in selenium-treated cells and that activated caspase-3 colocalized with terminal deoxynucleotidyltransferase dUTP nick end labeling-stained cells by immunofluorescence. Higher basal poly(ADP-ribose) polymerase (PARP) expression levels and PARP cleavage (a substrate for caspase-3) were observed during apoptosis in tumor cells, compared with normal cells. Selective tumor cell death was associated with an increase in sub-G0-G1 cells after propidium iodide staining and fluorescence-activated cell sorting analysis. SeMet caused an increase in arrest in the G2-M phase of the cell cycle selectively in cancer cells. Inhibition of cancer cell growth by SeMet was associated with phosphorylation of P-Tyr15-p34/cdc2, which caused growth arrest in the G2-M phase. Anchorage-independent growth of prostate cancer cells in soft agar was sensitive to selenium. Our results suggest that Na2SeO3 is the more potent inducer of apoptosis in normal and cancer prostate cells. Our SeMet results involving PARP and G2-M cell-cycle arrest (cited above) indicate that SeMet selectively induces apoptosis in cancer but not primary cells of the human prostate. Our overall findings are relevant to the molecular mechanisms of selenium actions on prostate carcinogenesis and help demonstrate the selective, dose-dependent effects of selenium (especially SeMet) on prostate cancer cell death and growth inhibition.
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PMID:Selenium effects on prostate cell growth. 1109 24


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