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 goals of this work were to establish a reproducible and effective model of apoptosis in a cell line derived from advanced prostate cancer and to study the role of the caspase family of proteases in mediating apoptosis in this system. The study involved the use of the prostate cancer cell line LNCaP. Apoptosis was induced using the hydroxymethyl glutaryl CoA reductase inhibitor, lovastatin, and was evaluated by agarose gel electrophoresis of genomic DNA, morphological criteria, and terminal deoxynucleotidyl transferase-mediated nick end labeling. Caspases were studied by catalytic activity, mRNA induction, and protein processing. Lovastatin (30 microM) was an effective inducer of apoptosis, causing changes that were evident after 48 h and essentially complete after 96-120 h of treatment. These effects were prevented by the simultaneous addition of mevalonate (300 microM) to the culture medium. Lovastatin induced a proteolytic activity that was able to cleave the enzyme poly(ADP-ribose) polymerase and the substrate Z-DEVD-AFC, which is modeled after the P1-P4 amino acids of the poly(ADP-ribose) polymerase cleavage site. Caspase-7, but not caspase-3, underwent proteolytic activation during lovastatin-induced apoptosis, an effect prevented by mevalonate. Caspase-7 was the only detected interleukin 1beta converting enzyme family protease with DEVD cleavage activity that exhibited lovastatin-induced mRNA up-regulation. Again, mevalonate blocked this effect. Lovastatin-induced apoptosis also was prevented when the caspase inhibitors Z-DEVD-CH2F or Z-VAD-CH2F (100 microM) where added to the medium. These studies have identified lovastatin as a powerful inducer of apoptosis in the cell line LNCaP. Caspase activation was a necessary event for LNCaP cells to undergo apoptosis during treatment with lovastatin. Of the caspases tested, only caspase-7 underwent proteolytic activation after stimulation with lovastatin. Identification of caspase-7 as a potential mediator of lovastatin-induced apoptosis broadens our knowledge of the molecular events associated with programmed cell death in a cell line derived from prostatic epithelium.
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PMID:Caspase-7 is activated during lovastatin-induced apoptosis of the prostate cancer cell line LNCaP. 942 61

Diazepam-binding inhibitor/acyl-CoA-binding protein (DBI/ACBP), a highly conserved 10-kDa polypeptide, has been implicated in various physiological processes including gamma-aminobutyric acid type A receptor binding, acyl-CoA binding and transport, steroidogenesis, and peptide hormone release. Both in LNCaP prostate cancer cells and 3T3-L1 preadipocytes, the expression of DBI/ACBP is stimulated under conditions that promote lipogenesis (treatment with androgens and insulin, respectively) and that involve the activation of sterol regulatory element-binding proteins (SREBPs). Accordingly, we investigated whether DBI/ACBP expression is under the direct control of SREBPs. Analysis of the human and rat DBI/ACBP promoter revealed the presence of a conserved sterol regulatory element (SRE)-like sequence. Gel shift analysis confirmed that this sequence is able to bind SREBPs. In support of the functionality of SREBP binding, coexpression of SREBP-1a with a DBI/ACBP promoter-reporter gene resulted in a 50-fold increase in transcriptional activity in LNCaP cells. Disruption of the SRE decreased basal expression and abolished SREBP-1a-induced transcriptional activation. In agreement with the requirement of a co-regulator for SREBP function, transcriptional activation by SREBP-1a overexpression was severely diminished when a neighboring NF-Y site was mutated. Cholesterol depletion or androgen treatment, conditions that activate SREBP function in LNCaP cells, led to an increase in DBI/ACBP mRNA expression and SRE-dependent transcriptional activation. These findings indicate that the promoter for DBI/ACBP contains a functional SRE that allows DBI/ACBP to be coregulated with other genes involved in lipid metabolism.
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PMID:Identification of diazepam-binding Inhibitor/Acyl-CoA-binding protein as a sterol regulatory element-binding protein-responsive gene. 968 28

Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, induces growth arrest in a variety of cancer cell lines. Its mechanism of action, however, has not been completely elucidated. E2F-1 is thought to act as an oncogene and a tumour suppressor, with its action probably dependent upon the cellular context. We have shown in this study that transcriptional regulation and proteasomal degradation of E2F-1 are critical regulatory events in lovastatin-induced cell death. Accompanying this is a reduction in the E2F-1-regulated expression of cell cycle genes such as c-myc, cyclin D1, cyclin A and cyclin B1. Cell cycle analysis demonstrated that the accumulation of apoptotic cells was preceded by a progressive decrease in the S-phase cell population in response to lovastatin. Although expression of E2F-1 was reduced in three prostate cancer cell lines-PC-3, LNCaP and DU-145-the p21 and p27 protein levels were not increased in all the cell lines treated, suggesting that increase in p21 and p27 protein expression per se is not responsible for lovastatin-mediated down-regulation of E2F-1. The subsequent apoptotic death of these cells in the presence of lovastatin can be prevented by forced ectopic expression of E2F-1. Taken together, these facts imply that E2F-1 is the target of an HMG-CoA inhibitor and critical cell death mediator in prostate cancer cells.
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PMID:Lovastatin-induced E2F-1 modulation and its effect on prostate cancer cell death. 1157 16

Breast and prostate cancer preferentially metastasize in the skeleton, inducing locally increased bone resorption by osteoclasts. Bisphosphonates (BPs), potent inhibitors of osteoclasts and bone resorption, are able to reduce metastatic bone lesions, but the metastasis-related cellular target molecules for BPs have not yet been identified. In osteoclasts, nitrogen-containing BPs inhibit the function of the mevalonate pathway, impairing the prenylation and activation of small GTPases. In addition, direct effects of BPs on cancer cells have been suggested. In the present study, the effects of two clinically used BPs, the amino-BP alendronate and clodronate, on adhesion, invasion, and migration of human PC-3 prostate cancer cells were examined in vitro. We also studied the possible role of the mevalonate pathway in invasion and migration of PC-3 cells using the beta-hydroxy-beta-methylglutaryl-CoA reductase inhibitor mevastatin and the mevalonate pathway intermediates mevalonate (mevalonic acid lactone), geranylgeraniol, and trans-trans-farnesol. The results demonstrate that alendronate pretreatment very effectively inhibited in vitro invasion of prostate cancer cells in a dose-dependent manner, with an IC50 as low as approximately 1 pM. The inhibition was similar to that of mevastatin. Clodronate also inhibited invasion, but the IC50 was 0.1 microM. Importantly, geranylgeraniol and trans-trans-farnesol reversed the inhibitory effect of alendronate and mevastatin but not the clodronate-induced inhibition of invasion. Alendronate pretreatment also inhibited migration, which was partially reversed by geranylgeraniol and trans-trans-farnesol. Adhesion of PC-3 cells to various matrices was reduced, and their F-actin organization was changed. Alendronate pretreatment also inhibited invasion of human Du-145 prostate and MDA-MB-231 breast cancer cells. As a conclusion, the results demonstrate that the mevalonate pathway leading to protein prenylation is important for cancer cell invasion and migration in vitro. They further suggest that interference with this pathway is involved in inhibition of invasion and migration of prostate cancer cells by the amino-BP alendronate but that the mechanism of clodronate inhibition is different. It is possible that BPs have therapeutic potential in preventing the spread of prostate cancer.
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PMID:Alendronate inhibits invasion of PC-3 prostate cancer cells by affecting the mevalonate pathway. 1508 15

Foamy gland and pseudohyperplastic carcinomas are two uncommon variants of prostate cancer and often pose diagnostic challenges on needle biopsies. Alpha-methylacyl-CoA-racemase (AMACR) is a recently discovered tumor marker whose expression is significantly upregulated in prostate cancer. However, the original works only studied ordinary prostate cancer without reference to specific morphologic variants. Therefore, the expression and diagnostic utility of AMACR in specific variants of prostate cancer are unknown. In addition, two different antibodies, one monoclonal and one polyclonal, were used in the previous studies. The goal of this study is to examine the expression pattern and diagnostic utility of AMACR in foamy gland and pseudohyperplastic prostate cancer and to compare the diagnostic utility of the two anti-AMACR antibodies in the same prostate needle biopsy series. Prostate cancer with foamy gland or pseudohyperplastic features was retrieved from the Johns Hopkins Hospital Surgical Pathology file. Thirty needle biopsies harboring prostate cancer with foamy gland features and 17 needle biopsies harboring prostate cancer with pseudohyperplastic features were available for this study. Immunohistochemistry for AMACR was performed with two antibodies, a monoclonal one (P504S) and a polyclonal one (AMACR-p), using previously published protocols. Immunohistochemistry for high molecular weight cytokeratin and p63 was performed to confirm the cancer diagnosis. The AMACR staining intensity was graded as negative, weak, moderate, and strong. Only the staining that was significantly stronger than that of background benign glands was considered positive. A total of 68% and 62% of foamy gland prostate cancer was positive for AMACR with P504S and AMACR-p antibodies, respectively. A total of 77% and 70% of pseudohyperplastic prostate cancer was positive for AMACR with P504S and AMACR-p antibodies, respectively. Staining was often heterogeneous with different staining intensities within the same lesion. The mean percentage of stained glands in positive cases was 74.4% (range 25-100%) with P504S and 78.9% (range 20-100%) with AMACR-p in foamy gland prostate cancer and 91% (range 10-100%) with P504S, and 86.7% (range 10-100%) with AMACR-p in pseudohyperplastic prostate cancer. Seven foci of high-grade prostatic intraepithelial neoplasia present in the study cases were all positive for AMACR. The two antibodies were not statistically different in their sensitivity and specificity. In conclusion, AMACR is potentially a useful diagnostic marker for foamy gland and pseudohyperplastic prostate cancer in the following setting. When the pathologist favors the diagnosis of these variants of cancer on routine stained sections and stains for basal cells are negative, yet still a definitive diagnosis of cancer is difficult because of the cancers' deceptively benign appearance, positive staining for AMACR can provide the additional confidence to establish a definitive malignant diagnosis. The major caveat in the interpretation of positive staining is that high-grade prostatic intraepithelial neoplasia cannot be in the differential diagnosis.
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PMID:Expression and diagnostic utility of alpha-methylacyl-CoA-racemase (P504S) in foamy gland and pseudohyperplastic prostate cancer. 1276 80

Alpha-methylacyl CoA racemase (AMACR), also known as P504S, plays an important role in peroxisomal beta-oxidation of branched-chain fatty acids. It has recently been shown that AMACR is highly expressed in prostate cancer and that it may be an important diagnostic marker for prostate carcinoma. However, little is known about expression of AMACR in normal tissues and other malignant tumors. In this study, we investigated expression of AMACR in 539 malignant tumors and 222 normal human tissues of various types by immunohistochemical analysis. mRNA levels of AMACR in normal organs and in selected tumors were assessed by real time PCR. In normal tissue, high expression of AMACR mRNA was identified in liver, kidney and salivary gland, while AMACR protein was detected in liver (hepatocytes), kidney (tubular epithelial cells), lung (only bronchial epithelial cells), and gallbladder (only mucosal epithelial cells). High expression of AMACR mRNA was found in prostate, liver, and kidney cancers but rarely in stomach and bladder cancers. A high percent of adenocarcinomas arising from these organs express AMACR, including 17 of 21 (81%) of hepatocellular carcinomas and 18 of 24 (75%) of renal cell carcinomas. In addition, carcinomas arising from tissues normally not expressing AMACR were also positive for the antigen, including 17 of 18 (94%) prostate carcinomas, 9 of 29 (31%) of urothelial carcinomas, and 4 of 15 (27%) of gastric adenocarcinomas. Two hundred and fifty cases of adenocarcinomas from lung, breast, pancreas, bile duct, adrenal gland, salivary gland, ovary, thyroid and endometrium were negative or rarely positive for AMACR. Neuroendocrine carcinomas rarely expressed AMACR. Melanomas, squamous cell carcinomas, basal cell carcinomas, soft tissue tumors (including epithelioid sarcomas and synovial sarcoma), thymomas, and germ cell tumors were negative for AMACR. Our data provide important baseline information for using AMACR in clinical practice and also are valuable in furthering understanding of the pathogenic role of AMACR in malignant neoplasms.
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PMID:Expression of alpha-methylacyl-CoA racemase (P504s) in various malignant neoplasms and normal tissues: astudy of 761 cases. 1764 May 55

Epidemiological studies have shown that consumption of red meat increases the risk of developing colon cancer. An enzyme, alpha-methylacyl CoA racemase (AMACR), also known as P504S, plays an important role in peroxisomal beta-oxidation of branched-chain fatty acids from red meat and dairy products. High expression of AMACR was recently found in prostate cancer. In this study, we investigated expression of AMACR in 242 cases of colonic tumors including 176 colorectal carcinomas, 38 colon adenomas and 28 hyperplastic (non-neoplastic) polyps by immunohistochemical analysis. The mRNA levels of AMACR expression in normal and colon cancer tissues were assessed by real-time PCR. Significant up-regulation of AMACR mRNA was found in colon carcinomas compared to normal tissue. There was very low or no expression of AMACR protein in normal colon, but AMACR was highly expressed in 76 and 75% of well and moderately differentiated colon carcinomas, respectively, and in 79% of adenomas. In contrast, only 4% of hyperplastic polyps expressed AMACR. Since this enzyme is involved in the metabolism of branched-chain fatty acids from beef, milk and dairy products, our results provide important molecular information regarding a possible link between diet and development of colon cancer. AMACR may also serve as a molecular marker for colon cancers and its precursor lesions.
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PMID:A dietary enzyme: alpha-methylacyl-CoA racemase/P504S is overexpressed in colon carcinoma. 1464 49

The diagnosis of prostatic adenocarcinoma remains dependent on the recognition of basic haematoxylin and eosin criteria. The discovery of alpha-methylacyl CoA racemase/P504S (AMACR/P504S) overexpression in prostate cancer represents a triumph of high throughput microarray technology, and is a powerful demonstration of how this methodology can be used to facilitate the rapid development of diagnostically relevant antibodies. Immunohistochemistry with anti-AMACR/P504S is useful for detecting prostate cancer in the full range of prostate specimens encountered in surgical pathology, be they needle biopsies, transurethral resection of prostate chips, or prostatectomies. In particular, studies to date with AMACR/P504S clearly demonstrate the ability of this marker to support a diagnosis of malignancy in prostate needle biopsies. This is particularly true when it is combined with negative staining for a basal cell marker, such as 34betaE12 or p63. Although it has limitations with respect to sensitivity and specificity, AMACR/P504S will no doubt become a standard adjunctive stain used by pathologists seeking to reach a definitive diagnosis in prostate biopsies considered to be atypical, but not diagnostic of malignancy on haematoxylin and eosin sections alone.
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PMID:Alpha-methylacyl CoA racemase (P504S): overview and potential uses in diagnostic pathology as applied to prostate needle biopsies. 1464 45

The ability to distinguish between aggressive and nonaggressive tumors has not changed despite vast improvements in the detection of prostate cancer (PCA). To improve predictive accuracy, additional PCA-specific biomarkers must be identified and it is the emerging microarray technology and gene expression profiling that appear to be capable of achieving this goal. Through comparisons of a number of published microarray studies of PCA, several potential biomarkers appear on the horizon, including the serine protease Hepsin, a-methylacyl CoA racemase, and the human homologue of the Drosophila protein Enhancer of Zeste. Although these markers will move toward validation by eventual protein expression studies, another aspect of microarray expression, global signature expression patterns through multidimensional scaling, appears to be promising in distinguishing between aggressive and nonaggressive forms of PCA or in distinguishing PCA from benign prostatic hyperplasia or normal prostate tissue.
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PMID:Molecular profiling of prostate cancer. 1473 37

Alpha-methyacyl-CoA racemase (AMACR), a mitochondrial and peroxisomal enzyme essential in lipid metabolism, is overexpressed in prostate cancer. Two different AMACR transcripts (designated IA and IIA), each derived from five exons, have been reported. AMACR IA, the most abundant form, encodes a 382-amino acid protein (Mw 42 kDa, pI 6.07). AMACR IIA contains an alternative fifth exon that has extensive homology to the human fumarate hydratase (FH) and encodes a 288-amino acid protein (Mw 32 kDa, pI 9.6). Here we report additional variants of IA and IIA whereby the transcripts lack exon 3 and are designated as IB (Mw 22 kDa, pI 10.31) and IIB (Mw 31 kDa, pI 9.44). Due to a frameshift, the alternative fifth exon in the IIA transcript encodes a polypeptide that differs from FH. In contrast, the IIB transcript, generated as a result of the dual alternative splicing events, encodes a polypeptide homologous with a highly conserved region of FH. We also identified a shorter variant form of IIA (IIAs, Mw 28 kDa, pI 9.65), which lacks the 5' half of the alternative fifth exon. The carboxy termini of all five gene products differ as a result of the alternative splicing events. In prostate tumor tissues that overexpressed AMACR, both the A and B forms were overexpressed, suggesting coregulation. Only the predominant AMACR IA has an acidic pI and contains the previously identified peroxisomal targeting signal (PTS1) peptide, while the other four variants are basic proteins that lack the peroxisomal targeting signal peptide. These observations have implications for the cellular localization and function of these AMACR variants.
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PMID:Alternative spliced variants of the alpha-methylacyl-CoA racemase gene and their expression in prostate cancer. 1496 Mar 64


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