Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have synthesized and studied the ability of a series of seven novel 1 alpha,25(OH)2 vitamin D3 analogues to inhibit clonal growth of prostate cancer cells (LNCaP, PC-3 and DU-145). Addition of double and triple bonds to the C/D ring (C-16) and side chain (C-22 and C-23) as well as lengthening of the side chain were important for enhanced activity against LNCaP and PC-3. Reorientation of the side chain in the 20-epi configuration resulted in analogues that were extremely potent only against LNCaP (ED50 approximately 5 x 10(-11) M). Compounds with six fluorines on the end of the side chain were very active against both PC-3 and LNCaP (ED50 approximately 2 x 10(-8) M). DU-145 cells were relatively resistant to compounds with all of these modifications, but removal of C-19 (e.g. 1,25(OH)2-16-ene-23-yne-26,27-F6-19-nor-D3) resulted in an analogue that was inhibitory against all three prostate cell lines. Further analysis showed that pulse exposure (3 days, 10(-7) M) to this analogue was enough to inhibit clonal growth of PC-3 cells by 50%. The same exposure also induced cell cycle arrest of all three cell lines, accompanied by upregulated protein expression of the cyclin-dependent kinase inhibitor (CDKI) known as p21waf1 in all three cell lines, and the CDKI known as p27kip1 in LNCaP cells. Associated with upregulation of these CDKIs, partial differentiation occurred as measured by increased expression of both prostate-specific antigen by LNCaP cells and E-cadherin, a cell adhesion protein that may act as a putative tumour suppressor (LNCaP and PC-3 cells). In summary, this is the first report of a potent series of 19-nor-vitamin D3 analogues with the ability to inhibit proliferation of LNCaP, PC-3 and DU-145 prostate cancer cell lines. These compounds may mediate their potent anti-proliferative activities through a cell cycle arrest pathway.
J Mol Endocrinol 1997 Aug
PMID:Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin. 927 57

We examined the in vivo effects of ONO-5046xNa, a specific neutrophil elastase (NE) inhibitor, on the growth of 2 non-small cell lung cancer cell lines, EBC-1 and PC-3, transplanted into severe combined immunodeficiency (scid) mice. The daily intraperitoneal injection of ONO-5046xNa (50 mg/kg/day) completely suppressed the tumor growth in EBC-1, a human squamous carcinoma cell line which produces immunoreactive NE. By contrast, in PC-3, a human adenocarcinoma cell line which is unable to produce immunoreactive NE, the ONO-5046xNa treatment caused delayed growth of the tumor. These findings suggest that ONO-5046xNa may have a clinical role in preventing the growth of human non-small cell lung cancer.
Res Commun Mol Pathol Pharmacol 1997 Aug
PMID:Neutrophil elastase inhibitor (ONO-5046-Na) inhibits the growth of human lung cancer cell lines transplanted into severe combined immunodeficiency (scid) mice. 934 34

We investigated the role of a neutrophil elastase (NE) produced by cancer cell lines on intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells using two human non-small cell lung cancer cell lines, EBC-1 and PC-3. It is known that immuno-reactive NE is produced by EBC-1 cells, but not PC-3. In control study, Northern blot analysis revealed that in vitro ICAM-1 mRNA transcripts in the rat endothelial cell line (WK-5) was increased in the presence of purified NE while a specific neutrophil elastase inhibitor (ONO-5046.Na) inhibited ICAM-1 expression. Similarly, ICAM-1 mRNA levels in WK-5 cells were increased by the culture supernatant obtained from EBC-1, but not from PC-3. In addition, ONO-5046.Na inhibited the increase in ICAM-1 mRNA levels stimulated by immuno-reactive HE from EBC-1. These results suggest that EBC-1 cells produce immunoreactive NE which has biological function of NE to stimulate ICAM-1 expression in the endothelial cells.
Res Commun Mol Pathol Pharmacol 1997 Oct
PMID:Adhesion molecule expression in vascular endothelial cells incubated with cancer cell line supernatant are inhibited by neutrophil elastase inhibitor (ONO-5046.Na). 943 21

FGF-1 mRNA is expressed in the prostate cancer cell lines LNCaP and PC-3 and in the breast carcinoma cell line MDA-MB-231. Levels of FGF-1 mRNA have been shown to be up-regulated by serum, phorbol esters, and combinations of growth factors. It was shown that the major FGF-1 mRNA species expressed following serum stimulation in MDA-MB-231 cells is FGF-1.C. To better understand the potential role of FGF-1 in human prostate and breast cancer, we began an analysis of the cis- and trans-acting elements of one of its promoters required for the serum, PMA, and androgen regulation in breast and prostate cancer cell lines. We show that FGF-1.C steady-state mRNA levels are increased following serum or PMA stimulation of PC-3 cells. Further, we determine the FGF-1.C transcription start site in PC-3 cells. By sequence analysis, we show that consensus AP1, AP2, and Sp1 sites and ARE- and CRE-near consensus elements are present in the immediate 5' region of the FGF-1.C transcription start site. Gel-shift assays show that oligonucleotides containing FGF-1.C AP1, AP2, or Spl sequences form specific DNA-protein complexes with nuclear extracts from PC-3 cells. To determine if these or other cis-acting sequences are responsible for the serum, androgen, or growth factor regulation of FGF-1 expression, fragments of the FGF-1.C promoter region were cloned upstream of the luciferase reporter gene. We show that FGF-1 synergizes with androgen to enhance FGF-1.C transcription in LNCaP cells. We further show that the DNA fragment containing sequence up to 1614 nucleotides upstream of the FGF-1.C transcription start site is sufficient for stimulating promoter activity following serum treatment of MDA-MB-231 cells. Thus, FGF-1.C promoter contains sequences that are important for androgen or serum stimulation in prostate and breast cancer cells.
J Steroid Biochem Mol Biol 1998 Aug
PMID:Regulation of a promoter of the fibroblast growth factor 1 gene in prostate and breast cancer cells. 971 43

Two human prostate adenocarcinoma cell lines, LNCaP and PC-3, were used to study the effect of 5-azacytidine on GGT gene expression, via genomic DNA methylation, and GSH content. When the cells were treated with 5-azaC, the specific GGT activity increased in a dose and time-dependent manner and was accompanied by the elevation of intracellular glutathione content. Southern blot analysis of DNA digested with MspI or HpaII showed negative correlation between the methylation pattern of GGT DNA and GGT activity, either in control or 5-azaC treated cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that GGT mRNA types I are expressed and induced in a cell type-specific manner in control and 5-azacC treated cells respectively. Overall, our investigations suggest that DNA methylation and other mechanisms combine to regulate GGT gene expression in studied prostate adenocarcinoma derived cells.
Biochem Mol Biol Int 1998 Oct
PMID:5-Azacytidine modulates gamma-glutamyltransferase and glutathione levels in two human prostatic adenocarcinoma cell lines. 980

Steroid-regulated gene transcription requires the coordinate physical and functional interaction of hormone receptors, basal transcription factors, and transcriptional coactivators. In this context ARA70, previously called RFG and ELE1, has been described as a putative coactivator that specifically enhances the activity of the androgen receptor (AR) but not that of the glucocorticoid receptor (GR), the progesterone receptor, or the estrogen receptor (ER). Here we describe the cloning of the cDNA for ELE1/ARA70 by RT-PCR from RNA derived from different cell lines (HeLa, DU-145, and LNCaP). In accordance with the previously described sequence, we obtained a 1845-bp PCR product for the HeLa and the LNCaP RNA. Starting from T-47D RNA, however, an 860-bp PCR product was obtained. This shorter variant results from an internal 985-bp deletion and is called ELE1beta; accordingly, the longer isoform is referred to as ELE1alpha. The deduced amino acid sequence of ELE1alpha, but not that of ELE1beta, differs at specific positions from the one previously published by others, suggesting that these two proteins are encoded by different nonallelic genes. ELE1alpha is expressed in the three prostate-derived cell lines examined (PC-3, DU-145, and LNCaP), and this expression is not altered by androgen treatment. Of all rat tissues examined, ELE1alpha expression is highest in the testis. This is also the only tissue in which we could demonstrate ELE1beta expression. Both ELE1alpha and ELE1beta interact in vitro with the AR, but also with the GR and the ER, in a ligand-independent way. Overexpression of either ELE1 isoform in DU-145, HeLa, or COS cells had only minor effects on the transcriptional activity of the human AR. ELE1alpha has no intrinsic transcription activation domain or histone acetyltransferase activity, but it does interact with another histone acetyltransferase, p/CAF, and the basal transcription factor TFIIB. The interaction with the AR occurs through the ligand-binding domain and involves the region corresponding to the predicted helix 3. Mutation in this domain of leucine 712 to arginine greatly reduces the affinity of the AR for ELE1alpha but has only moderate effects on its transcriptional activity. Taken together, we have identified two isoforms of the putative coactivator ARA70/ELE1 that may act as a bridging factor between steroid receptors and components of the transcription initiation complex but which lack some fundamental properties of a classic nuclear receptor coactivator. Further experiments will be required to highlight the in vivo role of ELE1 in nuclear receptor functioning.
Mol Endocrinol 1999 Jan
PMID:Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform. 989 17

The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) has been shown to induce apoptosis in various malignant cells including human prostate carcinoma cells (HPC). We examined several possible mechanisms by which 4HPR could induce apoptosis in HPC cells. 4HPR exhibited concentration- and time-dependent decrease in cell number both in androgen-dependent (LNCaP) and -independent (DU145 and PC-3) cells. The 4HPR concentrations causing 50% decrease in cell number in LNCaP, DU145, and PC-3 cultures were 0.9 +/- 0.16, 4.4 +/- 0.45, and 3.0 +/- 1.0 microM, respectively, indicating that LNCaP cells were more sensitive to 4HPR than the other cells. 4HPR-induced apoptosis in all three cell lines was evidenced by increased enzymatic labeling of DNA breaks and formation of a DNA ladder. 4HPR increased the level of reactive oxygen species, especially in LNCaP cells. 4HPR-induced apoptosis could be suppressed in LNCaP cells by antioxidant and in DU145 cells by a nuclear retinoic acid receptor-specific antagonist, suggesting the involvement of reactive oxygen species or retinoic acid receptors in mediating apoptosis induced by 4HPR in the different HPC cells. Furthermore, 4HPR modulated the expression levels of some apoptosis-related gene (p21, c-myc, and c-jun), which may also contribute to the induction of apoptosis by 4HPR in HPC cells.
Mol Pharmacol 1999 Mar
PMID:Induction of apoptosis by N-(4-hydroxyphenyl)retinamide and its association with reactive oxygen species, nuclear retinoic acid receptors, and apoptosis-related genes in human prostate carcinoma cells. 1005 23

Okadaic acid (OA), a toxin from the black sponge Halicondria okadai, is a specific inhibitor of serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A). OA is a tumor promoter but also induces apoptosis in some tumor cell lines. In this study, we determined whether ras mutation and/or p53 status are characteristics associated with the cell's sensitivity to the induction of apoptosis by OA. Several cell lines that differed in ras and p53 mutations were treated with OA (10-100 nM). At 24 to 48 h after treatment, the percentage of cells undergoing apoptosis was quantitated. The cell lines with mutations in either H-ras (human bladder carcinoma cell line T24 and mouse keratinocyte cell line 308), or K-ras (human colon carcinoma cell lines DLD-1 and HCT116; human prostate cancer cell lines LNCaP and PC-3; human lung cancer cell lines Calu-6 and SKLU-1; and human pancreatic cancer cell line MIAPaCa2) were more sensitive to OA-induced apoptosis (3- to 10-fold) than the cell lines that lacked the ras mutation (mouse epidermal cell lines C50 and JB6; murine fibroblast cell line NIH3T3; human colon cancer cell line HT29; human kidney epithelial cell line Hs715.K; and human pancreatic cancer cell line Bx-PC3). Similarly, using isogenic cell lines we found that overexpression of mutated H-ras in NIH3T3 and in SV40 immortalized human uroepithelial cells (SVHUC) enhanced their sensitivity to undergo apoptosis in response to OA treatment. The T24, DLD-1, SKLU-1, Calu-6, and MIAPaCa2 cell lines express mutated p53. The SVHUC as well as their ras-transfected counterparts have inactive p53 due to complex formation between large "T" antigen and p53. Taken together, these results imply that OA-induced apoptosis may involve a p53-independent pathway. The transfectants (NIH3T3-ras and SVHUC-ras), which express mutated H-ras, have up-regulated PP2A activity. OA treatment inhibited in vivo the levels of PP1 and PP2A activity, and induced apoptosis in SVHUC-ras and other cell lines. We conclude that OA-induced cell death pathway in ras-activated cell lines may involve a cross talk between PP1 and PP2A and ras signaling pathways. In light of the present results, the current theory that OA promotes mouse skin tumor formation by selective expansion of initiated cells that harbor ras mutations needs reevaluation.
Mol Pharmacol 1999 Sep
PMID:Ras mutation, irrespective of cell type and p53 status, determines a cell's destiny to undergo apoptosis by okadaic acid, an inhibitor of protein phosphatase 1 and 2A. 1046 39

Background: CD44, a major cell surface receptor for hyaluronic acid, is a family of ubiquitous cell surface glycoproteins. Altered levels of CD44 expression, seen in many epithelial neoplasms, have prognostic implications. Expression of standard and variant isoforms of CD44 was assessed in normal and neoplastic human prostate tissue and culture cells to evaluate as a marker for malignant transformation. Methods and Results: Expression of CD44s, CD44R, v5, v6, v7/8 and v10 was assessed in prostate tissue (benign and malignant) and cell lines (DU-145, PC-3, LNCaP, p69) and primary cultures of normal prostates and adenocarcinoma cells obtained from prostatectomies using reverse transcriptor polymerase chain reaction, Western blotting, and immunofluorescence. No CD44 expression was seen in LNCaP cells. p69, DU-145, and PC-3 cells expressed CD44s and CD44R. p69, cells demonstrated a 1000-bp-long form of CD44 mRNA, unique to this normal cell line. Both normal and neoplastic prostatic tissue demonstrated CD44s on Western blotting. Conclusions: In agreement with previous studies, prostatic adenocarcinoma cells, except LNCaP, expressed CD44s. Different patterns of CD44 expression were seen in benign and neoplastic prostate. Benign prostate exhibited higher v5 protein levels, whereas neoplastic prostates demonstrated higher CD44s expression. CD44s expression was identified in all neoplastic prostates as compared with only 50% of the benign prostates. No significant difference in expression of the other variants assessed (v6, v7, v7/8, and v10) was observed in the benign and neoplastic prostates.
Mol Diagn 1997 Sep
PMID:CD44 Expression in Benign and Neoplastic Human Prostates. 1046 10

In mammalian cells, the octamer motif (ATGCAAAT) binding proteins, Oct-1 and Oct-2, play an important role in the transcriptional transactivation of several ubiquitously expressed genes as well as cell-specifically expressed genes. To date, a role of the octamer binding proteins in damage-stimulated response is not known. In this report, we demonstrate that DNA-binding activity of Oct-1, as demonstrated by the electrophoretic mobility shift assay, is significantly induced in a dose-dependent manner upon treatment of human head and neck squamous carcinoma cells (PCI-04A) with ionizing radiation (5 Gy: 5-fold; 15 Gy: 11-fold). By comparison, activities of other transcription factors were modestly increased (15 Gy: AP-1, 2.5-fold; NF-kappaB, 2.6-fold; SP-1, 5-fold). Radiation stimulation of Oct-1 activity was also noted in two other human cancer cell lines, albeit to a lesser extent (MDA-MB231 breast carcinoma cells and PC-3 prostate carcinoma cells (5 Gy: approximately 2-fold). These data represent the first report of the activation of an octamer factor DNA binding activity in response to environmental cues and suggest a novel role of Oct-1 in the radiation signaling cascade in these cancer cells.
Mol Cell Biochem 1999 Sep
PMID:Ionizing radiation stimulates octamer factor DNA binding activity in human carcinoma cells. 1054 69


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