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)

Chromosomal deletion appears to be the earliest as well as the most frequent somatic genetic alteration during carcinogenesis. It inactivates a tumor suppressor gene in three ways, that is, revealing a gene mutation through loss of heterozygosity as proposed in the two-hit theory, inducing haploinsufficiency through quantitative hemizygous deletion and associated loss of expression, and truncating a genome by homozygous deletion. Whereas the two-hit theory has guided the isolation of many tumor suppressor genes, the haploinsufficiency hypothesis seems to be also useful in identifying target genes of chromosomal deletions, especially for the deletions detected by comparative genomic hybridization (CGH). At present, a number of chromosomal regions have been identified for their frequent deletions in prostate cancer, including 2q13-q33, 5q14-q23, 6q16-q22, 7q22-q32, 8p21-p22, 9p21-p22, 10q23-q24, 12p12-13, 13q14-q21, 16q22-24, and 18q21-q24. Strong candidate genes have been identified for some of these regions, including NKX3.1 from 8p21, PTEN from 10q23, p27/Kip1 from 12p13, and KLF5 from 13q21. In addition to their location in a region with frequent deletion, there are functional and/or genetic evidence supporting the candidacy of these genes. Thus far PTEN is the most frequently mutated gene in prostate cancer, and KLF5 showed the most frequent hemizygous deletion and loss of expression. A tumor suppressor role has been demonstrated for NKX3.1, PTEN, and p27/Kip1 in knockout mice models. Such genes are important targets of investigation for the development of biomarkers and therapeutic regimens.
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PMID:Chromosomal deletions and tumor suppressor genes in prostate cancer. 1208 61

Research into molecular and genetic mechanisms underlying prostate carcinogenesis would be greatly advanced by in vitro models of prostate tumors representing primary tumors. The generation of immortalized primary prostate cancer cells that will accurately reflect the in situ characteristics of malignant epithelium is greatly needed. We have successfully established a neoplastic immortalized human prostate epithelial (HPE) cell culture derived from a primary tumor. The RC-9 cells transduced through infection with a retrovirus vector expressing the E6 and E7 genes (E6E7) of human papilloma virus-16 (HPV-16) are currently growing well at passage 40, whereas RC-9 cells senesced at passage 7. RC-9/E6E7 cells exhibit epithelial morphology and high level of telomerase activity. More importantly, these immortalized cells produced tumors (SCID5038D) when inoculated into SCID mice. RC-9/E6E7 cells and SCID-5038D cells exhibit a high level of telomerase activity and androgen-responsiveness when treated with R1881. Expression of prostate specific antigen (PSA), androgen receptor (AR), prostate stem cell antigen (PSCA), an androgen-regulated prostate specific gene (NKX3.1), p16, cytokeratins 8, 15 and HPV-16 E6 gene was detected in both of these cells. RC-9/E6E7 and SCID5038D cells also showed growth inhibition when exposed to retinoic acid and transforming growth factor (TGF)-beta1, potent inhibitors of prostate epithelial cell growth. A number of chromosome alterations were observed including the loss of chromosomes 2p, 3p, 8p, 13, 14, 16, 17, 18, 21 and the gain of 7 and 20 in the tumor cell line (SCID5038D). These results demonstrate that this primary tumor-derived HPE cell line retained its neoplastic phenotypes and its prostate-specific markers and should allow studies to elucidate molecular and genetic alterations involved in prostate cancer. This is the first documented case of a malignant AR and PSA positive established human prostate cancer cell line from a primary tumor of a prostate cancer patient.
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PMID:A novel neoplastic primary tumor-derived human prostate epithelial cell line. 1273 99

The androgen receptor (AR) binds to and activates transcription of target genes in response to androgens. In an attempt to isolate cofactors capable of influencing AR transcriptional activity, we used an immunoprecipitation method and identified a 44-kDa protein, designated p44, as a new AR-interacting protein. p44 interacts with AR in the nucleus and with an androgen-regulated homeobox protein (NKX3.1) in the cytoplasm of LNCaP cells. Transient-transfection assays revealed that p44 enhances AR-, glucocorticoid receptor-, and progesterone receptor-dependent transcription but not estrogen receptor- or thyroid hormone receptor-dependent transcription. p44 was recruited onto the promoter of the prostate-specific antigen gene in the presence of the androgen in LNCaP cells. p44 exists as a multiprotein complex in the nuclei of HeLa cells. This complex, but not p44 alone, enhances AR-driven transcription in vitro in a cell-free transcriptional system and contains the protein arginine methyltransferase 5, which acts synergistically with p44 to enhance AR-driven gene expression in a methyltransferase-independent manner. Our data suggest a novel mechanism by which the protein arginine methyltransferase is involved in the control of AR-driven transcription. p44 expression is dramatically enhanced in prostate cancer tissue compared with adjacent benign prostate tissue.
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PMID:Purification and identification of a novel complex which is involved in androgen receptor-dependent transcription. 1297 18

Genetic studies have provided remarkable clues to the causes of prostate cancer (PCa). For example, in addition to the expected role of androgens in facilitating the development of PCa, the possibility that infections might lead to prostate cancer has been raised with the identification of RNASEL and MSR1 as familial prostate cancer genes; that insight will profoundly affect future studies and may ultimately lead to new approaches to the prevention of prostate cancer. The identification of key molecular alterations in prostate cancer cells implicates carcinogen defenses, including GSTP1, growth factor signaling pathways (such as NKX3.1, PTEN and p27) and androgens as critical determinants of the phenotype of PCa cells and defines specific targets for detection, diagnosis and treatment of PCa.
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PMID:Molecular mechanisms in prostate cancer. A review. 1521 88

Prostate cancer is the most frequently diagnosed neoplasia in men and one of the leading causes of cancer-related deaths in men over 60. In an effort to understand the molecular events leading to prostate cancer, we have identified PCAN1 (prostate cancer gene 1) (also known as GDEP), a gene that is highly expressed in prostate epithelial tissue and frequently mutated in prostate tumors. Here we demonstrate its expression in neural retina, and retinoblastoma cell culture but not retinal pigment epithelial cell culture. We further characterize PCAN1 expression in the prostate cell lines RWPE1, RWPE2, and LnCAP FGC. We demonstrate an increase in expression when the cells are grown in the presence of Matrigel, an artificial extracellular basement membrane. Expression was time dependent, with expression observed on d 6 and little or no expression on d 12. Testosterone was not found to increase PCAN1 expression in this culture system. In addition, normal prostate epithelial cells co-cultured with normal prostate stromal cells did not exhibit PCAN1 expression at any time. To definitively locate the transcription initiation sites, we performed restriction-ligase-mediated 5' RACE, to selectively amplify only mRNA with a 5' cap. An initial characterization of the sequence upstream of the initiation sites determined six possible binding sites for the prostate specific regulatory protein NKX3.1 and four potential binding sites for the PPAR/RXR heterodimer that is involved in the control of cell differentiation and apoptosis.
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PMID:Expression and initial promoter characterization of PCAN1 in retinal tissue and prostate cell lines. 1529 87

Understanding of molecular genetic mechanisms underlying prostate carcinogenesis would be greatly advanced by in vitro models of prostate tumors representing primary tumors. We have successfully established a neoplastic immortalized human prostate epithelial (HPE) clonal culture derived from a primary tumor of a prostate cancer patient (RC-58T) with hTERT, the catalytic subunit of telomerase. The early passage RC-58T cells derived from a radical prostatectomy specimen of a 52-year-old white male patient was transduced through infection with a retrovirus vector expressing the hTERT for the establishment of the RC-58T/hTERT cell line. One clonal line, soft-agar derived from the RC-58T/hTERT cell line, was isolated and further characterized phenotypically and genetically. These clonal (RC-58T/hTERT SA#4) cells are currently growing well at passage 70 and exhibit transformed morphology. The RC-58T/hTERT SA#4 line expressed a high level of telomerase activity and showed anchorage-independent growth in soft agar. The clonal line like the untransduced RC-58T cells (passage 3) expressed prostate specific antigen (PSA), androgen receptor (AR), prostate stem cell antigen (PSCA), and an androgen-regulated prostate specific gene NKX3.1, P16, and cytokeratin (CK) 8. Growth is slightly stimulated by dihydrotestosterone (DHT), and lyates are immunoreactive with AR antibody by Western blot analysis. More importantly, this clonal line produced adenocarcinomas when transplanted into SCID mice. A number of chromosome alterations were observed including the loss of chromosome Y, 1q, 2p, 3p, 4q, 8p, 11p, 14p, 17p and 18q. Our results demonstrate that this primary tumor-derived HPE cell line retained its neoplastic phenotypes and its prostate specific markers and should allow elucidating molecular and genetic alterations involved in prostate cancer. This is the first documented case of an AR and PSA expressing telomerase established human prostate cancer cell line with neoplastic phenotypes from a primary tumor of a prostate cancer patient.
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PMID:A telomerase-immortalized primary human prostate cancer clonal cell line with neoplastic phenotypes. 1537 56

We sought preclinical data on the cellular and molecular effects of dutasteride in androgen-responsive, human prostate cancer (PCa) cells to better understand the mechanisms of action of 5 alpha-reductase inhibition in these cells. We used the human prostate cancer cell line LNCaP, which exhibits most features of PCa cells including androgen responsiveness. Our findings show that dutasteride kills PCa cells in vitro; it dramatically reduced viability and proliferation and disrupted genes and cellular pathways involved in metabolic, cell cycle, and apoptotic responses besides those expected in androgen-signaling pathways. Microchip gene array expression analysis revealed activation of genes in the FasL/tumor necrosis factor alpha (TNF-alpha) apoptotic and cell-survival pathways, correlating with the growth and survival effects in the LNCaP cells. Real-time polymerase chain reaction confirmed expression level changes seen by microarray analysis of candidate genes such as PLA2G2A, CDK8, CASP7, MDK, and NKX3.1. Collectively, our findings delineate the cellular and molecular effects of dutasteride in androgen-responsive PCa cells in vitro and may lead to its better therapeutic and chemopreventive use in PCa.
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PMID:Gene expression in prostate cancer cells treated with the dual 5 alpha-reductase inhibitor dutasteride. 1547 68

In a strategy aimed at identifying novel markers of human prostate cancer, we performed expression analysis using microarrays of clones randomly selected from a cDNA library prepared from the LNCaP prostate cancer cell line. Comparisons of expression profiles in primary human prostate cancer, adjacent normal prostate tissue, and a selection of other (nonprostate) normal human tissues, led to the identification of a set of clones that were judged as the best candidate markers of normal and/or malignant prostate tissue. DNA sequencing of the selected clones revealed that they included 10 genes that had previously been established as prostate markers: NKX3.1, KLK2, KLK3 (PSA), FOLH1 (PSMA), STEAP2, PSGR, PRAC, RDH11, Prostein and FASN. Following analysis of the expression patterns of all selected and sequenced genes through interrogation of SAGE databases, a further three genes from our clone set, HOXB13, SPON2 and NCAM2, emerged as additional candidate markers of human prostate cancer. Quantitative RT-PCR demonstrated the specificity of expression of HOXB13 in prostate tissue and revealed its ubiquitous expression in a series of 37 primary prostate cancers and 20 normal prostates. These results demonstrate the utility of this expression-microarray approach in hunting for new markers of individual human cancer types.
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PMID:Expression analysis onto microarrays of randomly selected cDNA clones highlights HOXB13 as a marker of human prostate cancer. 1558 92

NKX3.1 is a prostate-specific homeoprotein and tumor suppressor that is affected by the loss of 8p21 in prostate cancer. In mice, Nkx3.1 haploinsufficiency results in prostatic dysplasia and complements cancer formation induced by loss of other suppressor genes. However, NKX3.1 expression can be immunohistochemically detected in most primary prostate cancers. We examined the relationship between suppressor gene haploinsufficiency, methylation, and quantitative NKX3.1 expression levels in primary prostate cancer. NKX3.1 gene copy number was assessed by microsatellite analysis, fluorescence in situ hybridization, and quantitative PCR. NKX3.1 gene methylation was determined in prostate cancer cell lines and we thereby identified potential CpG methylation sites for methylation-specific PCR analysis in tissues. We validated and then applied an internally controlled fluorescence immunomicroscopic assay for NKX3.1 protein expression in 48 primary prostate cancer specimens from radical prostatectomies. NKX3.1 loss of heterozygosity was found in 27 of 43 tissues tested. Classic CpG island methylation of the NKX3.1 gene was not found in either prostate cancer cell lines or tissues. However, in 33 of 40 samples tested, CpG sites at -921, -903, and -47 were methylated to a greater degree in malignant than in adjacent normal cells. In 43 of 48 samples, NKX3.1 protein expression was reduced from 0.34 to 0.90 compared with adjacent normal luminal epithelium (mean of all samples, 0.68; 95% confidence interval, 0.05). In 12 cases that also had high-grade prostatic intraepithelial neoplasia, NKX3.1 expression levels were similar in preinvasive and invasive cancer cells and significantly lower than adjacent normal cells. Even in the presence of allelic loss, NKX3.1 expression is reduced over a wide range in prostate cancer at the time of prostatectomy, suggesting that diverse factors influence expression. Samples with protein expression below the median level in cancer cells had both NKX3.1 deletion and selective CpG methylation.
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PMID:Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer. 1573 99

NKX3.1 is an androgen-regulated prostate-specific homeobox gene that is thought to play an important role in prostate development and cancerogenesis. NKX3.1 acts as a tumor suppressor gene specifically in the prostate. Up-regulation of NKX3.1 gene offers a promising gene therapy for prostate cancer. The decoy strategy has been developed and is considered a useful tool for regulating gene expression and gene therapy. In our previous studies, we identified a 20 bp inhibitory element upstream of the NKX3.1 promoter. In this study, we focused on using the 20 bp inhibitory element decoy to block negative regulation of the NKX3.1 gene and to up-regulate NKX3.1 expression using synthetic double-stranded oligodeoxynucleotides of the 20 bp inhibitory element. We found in an electrophoretic mobility shift assay experiment that the 20 bp inhibitory decoy presented competitive binding to a specific binding protein of the 20 bp inhibitory element in prostate cancer cell line LNCaP. In luciferase reporter gene assays, we found that the 20 bp inhibitory decoy could enhance NKX3.1 promoter activity, and RT-PCR and Western blot analysis revealed that NKX3.1 expression was up-regulated effectively by the transfection with the 20 bp inhibitory decoy. Furthermore, cell proliferation was inhibited by up-regulated NKX3.1 expression induced by the 20 bp inhibitory decoy.
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PMID:Up-regulation of NKX3.1 expression and inhibition of LNCaP cell proliferation induced by an inhibitory element decoy. 1588 Feb 62


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