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)

Many tumour types have been reported to have deletion of 9p21 (refs 1-6). A candidate target suppressor gene, p16 (p16INK4a/MTS-1/CDKN2), was recently identified within the commonly deleted region in tumour cell lines. An increasing and sometimes conflicting body of data has accumulated regarding the frequency of homozygous deletion and the importance of p16 in primary tumours. We tested 545 primary tumours by microsatellite analysis with existing and newly cloned markers around the p16 locus. We have now found that small homozygous deletions represent the predominant mechanism of inactivation at 9p21 in bladder tumours and are present in other tumour types, including breast and prostate cancer. Moreover, fine mapping of these deletions implicates a 170 kb minimal region that includes p16 and excludes p15.
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PMID:Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. 755 Mar 53

Fluorescence in situ hybridization has emerged as an extremely important tool for detection and characterization of nonrandom chromosome aberrations in cancer. Fluorescence in situ hybridization assays have been very reliable in cytogenetic tumor preparations, but have been more unpredictable in archival, paraffin-embedded specimens. We describe novel approaches for detection of chromosome aberrations in frozen tumor specimens, touch preparations, and cytological preparations. These approaches are both simple and reproducible, with minimal case-to-case variation in hybridization efficiency or hybridization signal quality. We demonstrate potential applications of these novel approaches by evaluating: 1) significance of normal karyotypes in malignant peripheral nerve sheath tumors; 2) p15/p16 copy number in prostate cancer; and 3) clonal chromosome 3p deletion in cytological preparations of pleural fluid from patients with mesothelioma.
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PMID:Novel fluorescence in situ hybridization approaches in solid tumors. Characterization of frozen specimens, touch preparations, and cytological preparations. 757 65

TGF-beta1 is a potent negative regulator of cell growth that transduces signals through interaction with type I and type II receptors that form a heteroduplex. Abnormal expression and mutational alterations of these receptors have recently been shown in several human malignancies. In previous studies, we have demonstrated reduced expression of both types of transforming growth factor (TGF) beta1 receptors in human prostate tumors. In this study, using the human prostate cancer cell line, LNCaP, which is refractory to TGF-beta1 and lacks type II receptor (R-II), we investigated whether overexpression of the R-II receptor can restore sensitivity to the negative growth effects of TGF-beta1. LNCaP cells were transfected with plasmid containing the full length of human TGF-beta R-II receptor cDNA sequence. Stable transfectant clones were selected for R-II mRNA and protein expression by Northern and Western analyses, respectively. The effect of TGF-beta on LNCaP R-II overexpressing clones was examined on the basis of: (a) growth inhibition (cell number); (b) DNA synthesis using the [3H]thymidine incorporation assay; (c) induction of cyclin-dependent-kinase inhibitors, p21WAF-1/Cip1, p27Kip1, and p15; and (d) colony-forming ability in soft agar. Both the cell number and the rate of DNA synthesis of R-II-overexpressing clones were significantly suppressed by exogenous TGF-beta1 in a dose-dependent manner, compared with control cell lines. Treatment of R-II cloned transfectants with TGF-beta1 induced a G1 arrest, which was accompanied by a transient increase in p21WAF-1/Cip1 and p27Kip1 expression at the mRNA and protein level. Furthermore, the LNCaP R-II transfectants analyzed exhibited a markedly reduced colony-forming ability. Our results indicate that overexpression of TGF-beta1 R-II receptor in LNCaP prostate cancer cells caused tumor growth inhibition by restoring the TGF-beta signaling mechanism and TGF-beta1 sensitivity.
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PMID:Overexpression of transforming growth factor (TGF) beta1 type II receptor restores TGF-beta1 sensitivity and signaling in human prostate cancer cells. 948 55

Neoplastic transformation, cancer progression, and metastasis are determined by a series of well-defined changes that take place in target tissue cells. Genetic alterations associated with human prostate carcinogenesis are not well defined. Some chromosomal changes, including gain of chromosomes 7, 12, 17, and X and loss of heterozygosity in chromosomes 8p, 10q, 16q, 17p, and 18q, have been reported. We examined five newly established and eight previously established prostate cancer cell lines before and after subcutis and orthotopic injection into nude mice and observed that structural alterations of chromosome 5 were present in all of the cell lines except the parental LNCaP. The fluorescence in situ hybridization preparations with the use of whole chromosome 5 DNA painting probe confirmed our Giemsa-banding data. Alterations of chromosome 5 consisted of t(1;5)(p36;q15), t(5;?)(p11;?), del(5)(q23q35) in the SP2964(= ARCaP) cell line; t(5;8)(p15;q12), i(5)(p10), t(5;15)(q11;p11) in the SP3031 cell line; t(5;?;15) (q15;?;p11), t(5;7;14)(q31;p11-q32;q11), in the SP3173 and SP3241 cell lines (derived from the same patient); del(5)(q23-33) and t(5;7;14)(q31;p11-q32;q11) in the SP3316 cell line; t(3;5)(q21;q35) in the SP2884 cell line; t(5;5)(p15;q11) in the SP2356 cell line; i(5)(p10),t(5;?)(q23;?) in the DU-145 cell line; and i(5)(p10), t(5;?)(q11;?) and t(2;5)(q15;q15) in the PC-3 cell line. Because, in most cases, alteration of chromosome 5 resulted in the partial or complete loss of 5q, we conjectured that 5q might contain one or more tumor-suppressor genes for human prostate cancer development.
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PMID:Structural alterations of chromosome 5 in twelve human prostate cancer cell lines. 979 73

Cellular senescence has been proposed to be an in vitro and in vivo block that cells must overcome in order to immortalize and become tumorigenic. To characterize these pathways, we focused on changes in the cyclin-dependent kinase inhibitors and their binding partners that underlie the cell cycle arrest at senescence. As a model, we utilized normal human prostate epithelial cell (HPEC) and human uroepithelial cell (HUC) cultures. After 30-40 population doublings cells became growth-arrested in G0/1 with a threefold decrease in Cdk2-associated activity, a point defined as pre-senescence. Temporally following this growth arrest, the cells develop a senescence morphology and express senescence-associated beta-galactosidase (SA-beta-gal). Levels of p16(INK4a) and p57(KIP2) rise in HUCs during progressive passages, whereas only p16 increases in HPEC cultures. The induced expression of p57, similar to p16, produces a senescent-like phenotype. pRB, cyclin D, p19(INK4d) and p27(KIP1) decrease in both cell types. We find that p53, p21(CIP1) and p15(INK4b) are transiently elevated in HPECs and HUCs at the pre-senescent growth arrest, then return to low proliferating levels at terminal senescence. Analysis of p53, p21(CIP1), p15(INK4b), p16(INK4a), and p57(KIP2) reveals altered expression in immortalized, non-tumorigenic HPV16 E6 and E7 prostate lines and in tumorigenic prostate cancer cells. These results indicate: (i) the existence of a subset of growth inhibiting genes elevated at the onset of the senescence, (ii) a distinct class of genes involved in the maintenance of senescence, and (iii) the frequent inactivation of these pathways during immortalization.
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PMID:Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. 1178 34

Synthetic retinoid-related molecules, such as N-(4-hydroxyphenyl)retinamide (fenretinide) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induce apoptosis in a variety of malignant cells. The mechanism(s) of action of these compounds does not appear to involve retinoic acid receptors (RARs) and retinoid X receptors (RXRs), although some investigators disagree with this view. To clarify whether some retinoid-related molecules can induce apoptosis without involving RARs and/or RXRs, we used 4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-E-propenyl] benzoic acid (AGN193198) that neither binds effectively to RARs and RXRs nor transactivates in RAR- and RXR-mediated reporter assays. AGN193198 potently induced apoptosis in prostate, breast, and gastrointestinal carcinoma cells and in leukemia cells. AGN193198 also abolished growth (by 50% at 130-332 nM) and induced apoptosis in primary cultures established from prostatic carcinoma (13 patients) and gastrointestinal carcinoma (1 patient). Apoptosis was induced rapidly, as indicated by mitochondrial depolarization and DNA fragmentation. Molecular events provoked by AGN193198 included activation of caspase-3, -8, -9, and -10 (by 4-6 h) and the production of BID/p15 (by 6 h). These findings show that caspase-mediated induction of apoptosis by AGN193198 is RAR/RXR-independent and suggest that this compound may be useful in the treatment of prostate cancer.
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PMID:A retinoid-related molecule that does not bind to classical retinoid receptors potently induces apoptosis in human prostate cancer cells through rapid caspase activation. 1512 74

Benign prostate hyperplasia and prostate cancer are major public health problems. We report herein that daily treatment of male rats with 50, 100 or 150 mg quercetin per kg body weight resulted in serum concentrations of quercetin equivalent to 25.3 microM, 43.3 microM and 54.3 microM respectively. Concomitantly, serum testosterone levels were increased by 1.79-, 1.83- and 3.48-fold, while serum dihydrotestosterone (DHT) levels were 125%, 92% and 73% of the control. A slight increase in prostate weight coupled with dilated prostate lumens full of secretory materials were observed. Finasteride alone caused a significant decrease in serum DHT level and prostate weight. Co-administration of quercetin with finasteride prevented the finasteride-induced decrease in serum DHT levels but significantly enhanced the reduction in wet prostate weight, which was reduced by 26.9% in finasteride-treated animals to 31.8%, 40.0% and 48.2% after finasteride given together with the three doses of quercetin. The combined treatment altered cell cycle-regulated proteins in a wide spectrum. The expressions of cyclin D1, CDK-4, cdc-2 and phospho-cdc-2 at tyrosine 15, phospho-MEK1/2, phospho-MAP kinase, phospho-pRb at serine 780 and serine 807/811 were significantly inhibited, while the levels of p15, p21 and p27 were increased. In conclusion, quercetin-finasteride treatments caused wide cell cycle deregulation in rat prostates, which, in turn, decreased the proliferation rate, changed the secretion activities of epithelial cells and resulted in a marked reduction in wet prostate weight. The results suggest that quercetin synergizes with finasteride to reduce the wet prostate weight through a cell cycle-related pathway, which may be androgen independent.
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PMID:Reduction of rat prostate weight by combined quercetin-finasteride treatment is associated with cell cycle deregulation. 1571 25

The development of age-related proliferative disorders of the prostate gland is supported by transdifferentiation and cellular senescence processes in the stroma. Both processes are involved in remodeling of stromal tissue, as observed in benign prostatic hyperplasia (BPH), and in "reactive stroma" adjacent to prostate cancer (PCa). It has been assumed that TGF-beta1 plays a key role in the aging prostate by inducing premature senescence and favoring myofibroblast differentiation. Therefore, we evaluated the stromal cell phenotypes of human primary adult prostatic fibroblasts (n=3) and the molecular and cellular mechanisms of growth arrest after treatment with TGF-beta1 and of in vitro cellular senescence. Microarray analysis, quantitative PCR, immunofluorescence and western blot revealed that cellular senescence and transdifferentiation of fibroblasts have distinct underlying mechanisms, pathways and gene and protein expression profiles in human PrSCs. In clear contrast to senescent cells, TGF-beta1-treated cells morphologically transdifferentiated into myofibroblasts with dense cytoskeletal fibers and increased expression of smooth muscle cell alpha-actin, calponin and tenascin. TGF-beta1 induced neither expression of senescence-associated markers nor genes involved in terminal growth arrest, such as senescence-associated beta-galactosidase and cyclin-dependent kinase (cdk) inhibitors p16(Ink4A) and p21(Cip1) but increased p15(Ink4B) protein expression. Differentiation inhibitor (Id-1) protein level down-regulation was observed under both conditions. Genes specifically up-regulated by transdifferentiation but not by cellular senescence of PrSCs were metalloproteinase 1 tissue inhibitor (Timp1), transgelin (Tagln), gamma 2 actin (Actg2), plasminogen activator inhibitor 1 (Serpinel), insulin-like growth factor binding protein 3 (Igfbp3), parathyroid hormone-like hormone (Pthlp), Tgfb-1, four and a half LIM domains 2 (Fhl-2), hydrogen peroxide-inducible clone 5 (Hic5) and cartilage oligomeric matrix protein (Comp). Other genes, such as Cdc28 protein kinase 1 (Cks1b), v-myb myeloblastosis viral oncogene homolog (MybL2), pyruvate kinase, muscle 2 (Pkm2) and Forkhead box M1 (FoxM1), were down-regulated only upon TGF-beta1 treatment but not by cellular senescence. Pyruvate dehydrogenase kinase 3 (Pdk3) and connective tissue growth factor (Ctgf) were up-regulated and hyaluronan synthase 3 (Has3) down-regulated under both conditions. Moreover, GageC1, a prostate/testis-specific protein overexpressed in symptomatic BPH and PCa was induced in transdifferentiated stromal cells. Genes such as GageC1 could be promising targets for therapeutic inhibitors of stromal tissue remodeling and progression of BPH and PCa.
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PMID:Profiling molecular targets of TGF-beta1 in prostate fibroblast-to-myofibroblast transdifferentiation. 1561 Jul 63

Indole-3-carbinol (I3C) is produced by members of the family Cruciferae, and particularly members of the genus Brassica (e.g., cabbage, radishes, cauliflower, broccoli, Brussels sprouts, and daikon). Under acidic conditions, 13C is converted to a series of oligomeric products (among which 3,3'-diindolylmethane is a major component) thought to be responsible for its biological effects in vivo. In vitro, 13C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer, and leukemic cells; induce G1/S arrest of the cell cycle, and induce apoptosis. The cell cycle arrest involves downregulation of cyclin D1, cyclin E, cyclin- dependent kinase (CDK)2, CDK4, and CDK6 and upregulation of p15, p21, and p27. Apoptosis by I3C involves downregulation antiapoptotic gene products, including Bcl-2, Bcl-xL, survivin, inhibitor-of-apoptosis protein (IAP), X chromosome-linked IAP (XIAP), and Fas-associated death domain protein-like interleukin-1-beta-converting enzyme inhibitory protein (FLIP); upregulation of proapoptotic protein Bax; release of micochondrial cytochrome C; and activation of caspase-9 and caspase-3. This agent inhibits the activation of various transcription factors including nuclear factor-kappaB, SP1, estrogen receptor, androgen receptor and nuclear factor-E2-related factor 2 (Nrf2). This indole potentiates the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through induction of death receptors and synergises with chemotherapeutic agents through downregulation of P-glycoprotein (P-gp). In vivo, I3C was found to be a potent chemopreventive agent for hormonal-dependent cancers such as breast and cervical cancer. These effects are mediated through its ability to induce apoptosis, inhibit DNA-carcinogen adduct formation, and suppress free-radical production, stimulate 2-hydroxylation of estradiol, inhibit invasion and angiogenesis. Numerous studies have indicated that I3C also has a strong hepatoprotective activity against various carcinogens. Initial clinical trials in women have shown that I3C is a promising agent against breast and cervical cancers.
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PMID:Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. 1608 11

Prostate carcinoma is a hormonally driven age-related neoplasm. Cellular senescence is an age-related process where cells remain metabolically active but in a growth-arrested state at the G1 phase. p14(ARF), p15(INK4b), and p16(INK4a), which are known to regulate G1 cell cycle arrest, and the tumor necrosis factor receptor superfamily member decoy receptor 2 (DCR2), have been recently identified as senescence markers. The purpose of this study was to characterize and compare the expression of p14(ARF), p15(INK4b), p16(INK4a), and DCR2 in tissue microarrays containing cases of normal prostate, nodular hyperplasia, prostate intraepithelial neoplasia (PIN), and malignant prostate cancer tissue. We performed immunohistochemical staining for p14(ARF), p15(INK4b), p16(INK4a), and DCR2 in tissue microarray blocks containing 41 cores of normal prostate, 65 cores of nodular hyperplasia, 21 cores of PIN, 69 cores of low-grade prostate carcinoma, and 42 cores of high-grade prostate carcinoma, derived from 80 cases of prostatectomy with adenocarcinomas. We detected positive staining of p16(INK4a) in 19% of the PIN, 25% of the low-grade carcinoma, and 43% of the high-grade carcinoma specimens but none in the normal prostate and nodular hyperplasia specimens. Expression of p14(ARF) revealed very high levels of expression in normal tissues (83%), nodular hyperplasia (88%), PIN (89%), and cancer cells (100%). P15(INK4b) and DCR2 were found positive in 81 and 33% normal, 46 and 10% nodular hyperplasia, 74 and 36% PIN tissues, 87 and 89% low-grade carcinomas, and 100 and 93% high-grade carcinomas. There is an increased protein expression of senescence-associated molecular markers, indicating that cellular senescence might play a role in prostate carcinoma. Because p16(INK4a)-positive cells were detected only in premalignant lesions and carcinomas but not in normal or benign tissues, p16(INK4a) may aid in the diagnosis of PIN and prostate cancer in difficult cases.
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PMID:Expression of p14ARF, p15INK4b, p16INK4a, and DCR2 increases during prostate cancer progression. 1679 75


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