Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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

In the present study, we examined the effects of over-expression of the potential tumor suppressor gene IGFBP-rP1/mac25 on cell-cycle kinetics in prostate cancer cells. The majority of the high expressing IGFBP-rP1/mac25 cell population was located in the G1 and sub-G0/G1 peaks; synchronizing cells in G2/M with nocodazole demonstrated the high expressing IGFBP-rP1/mac25 clones were delayed in the G1 phase of the cell cycle. Unscheduled expression of cyclin A in the sub-G0/G1 peak occurred in the IGFBP-rP1/mac25 clones. Immunoblots showed decreased cyclin D1 and p21 and increased cyclin E, p16, and p27 in the high expressing IGFBP-rP1/mac25 clones compared to the control cells. Cyclin D1/cdk-4,6 and cyclin E/cdk-2 kinase activities decreased but cyclin A/cdk-2 kinase activity increased for the high expressing IGFBP-rP1/mac25 clones compared to control cells. A pRb immunoprecipitation demonstrated more binding of E2F-1 to pRb in the high expressing IGFBP-rP1/mac25 clones than in control cells. Finally, cell senescence, as assessed by senescence-associated beta-galactosidase, demonstrated significantly more staining in the IGFBP-rP1/mac25 cells than control cells. These results suggest that IGFBP-rP1/mac25 alters the cell cycle kinetics of the M12 prostate cell line by delaying the cells in the G1 phase of the cell cycle. In addition, the appearance of cyclin A in the sub-G0/G1 phase of the cell cycle and the increased kinase activity of cyclin A/cdk-2 in the IGFBP-rP1/mac25 clones suggests that cyclin A is associated with the apoptotic cells.
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PMID:Over-expression of insulin-like growth factor binding protein-related protein-1(IGFBP-rP1/mac25) in the M12 prostate cancer cell line alters tumor growth by a delay in G1 and cyclin A associated apoptosis. 1179 Nov 84

It has been suggested that the helix-loop-helix protein Id-1 plays an important role in tumourigenesis in certain types of human cancer. Previously, we reported that Id-1 was up-regulated during sex hormone-induced prostate carcinogenesis in a Noble rat model (Ouyang et al. (2001) Carcinogenesis, 22, 965-973). In the present study, we investigated the direct effect of Id-1 expression on human prostate cancer cell proliferation by transfecting an Id-1 expression vector into a prostate cancer cell line LNCaP. Ten stable transfectant clones were isolated and the ectopic Id-1 expression resulted in both increased DNA synthesis rate and the percentage of S phase cells. To study the possible mechanisms involved in the Id-1 induced prostate cancer cell growth, we examined the expression of several factors responsible for G(1) to S phase progression. We found that Id-1 expression induced phosphorylation of RB and down-regulation of p16(INK4a) but not p21(Waf1)or p27(Kip1). Our results indicate that the Id-1 induced inactivation of p16(INK4a)/pRB pathway may be responsible for the increased cell proliferation in prostate cancer cells. Given the fact that both Id-1 over-expression and inactivation of p16(INK4a)/pRB are common events in prostate cancer, our results provide a possible mechanism on the molecular basis of prostate carcinogenesis.
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PMID:Id-1 stimulates serum independent prostate cancer cell proliferation through inactivation of p16(INK4a)/pRB pathway. 1201 43

The human INK4a gene locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p14(ARF), which are frequently inactivated in human cancer. Whereas p16(INK4a) acts through engagement of the Rb-cdk4/6-cyclin D pathway, both the pro-apoptotic and cell cycle-regulatory functions of p14(ARF) were shown to be primarily dependent on the presence of functional p53. Recent reports have also implicated p14(ARF) in p53-independent mechanisms of cell cycle regulation and apoptosis induction, respectively. To further explore the pro-apoptotic function of p14(ARF) in relation to functional cellular p53, we constructed a replication-deficient adenoviral vector for overexpression of p14(ARF) (Ad-p14(ARF)). As expected, Ad-p14(ARF) efficiently induced apoptosis in p53/Rb wild-type U-2OS osteosarcoma cells at low multiplicities of infection. Interestingly, Ad-p14(ARF) also induced apoptosis in both p53-deleted SAOS-2 osteosarcoma cells and HCT116 colon cancer cells with a bi-allelic knock-out of p53 (HCT116-p53(-/-)). Similarly, adenovirus-mediated overexpression of p14(ARF) induced apoptosis in p53/Bax-mutated DU145 prostate cancer cells as well as in HCT116 cells devoid of functional Bax (HCT116-Bax(-/-)). Restoration of Bax expression by retroviral gene transfer in DU145 cells did not further enhance p14(ARF)-triggered cell death. Infection with Ad-p14(ARF) induced activation of mitochondrial permeability shift transition, caspase activation and apoptotic DNA fragmentation irrespective of the presence or absence of either Bax or functional cellular p53. Nevertheless, overexpression of the anti-apoptotic Bcl-2 homolog Bcl-x(L) markedly inhibited p14(ARF)-induced apoptosis. This may indicate that p14(ARF) triggers a so far unknown activator of mitochondrial apoptosis which can be inhibited by Bcl-2 but which acts either independently or downstream of Bax. Taken together, this report demonstrates the participation of signaling pathways apart from the p53/Mdm-2 rheostat and Bax in p14(ARF)-mediated apoptosis.
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PMID:Adenovirus-mediated overexpression of p14(ARF) induces p53 and Bax-independent apoptosis. 1208 30

We examined the status of a cell cycle checkpoint by immunohistochemically staining for p16 and pRb using multiple tissue arrays generated from 49 primary and 23 hormone-sensitive metastatic human prostate cancers. We find that p16, a cell cycle inhibitor, is paradoxically overexpressed in 83% of proliferating primary prostate cancers and increased expression correlates with a more rapid treatment failure (P=0.01) and a higher histologic grade (P=0.001). pRb staining is heterogeneous, loses expression infrequently (19%), and does not correlate with p16 expression. Loss of either p16 or pRb expression is found significantly (P=0.01) more commonly (55%) in metastatic specimens. The remarkable frequency of p16/pRb alterations and strong clinical associations implicates inactivation of this pathway as a critical determinant in prostate cancer progression.
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PMID:Alterations in the p16/pRb cell cycle checkpoint occur commonly in primary and metastatic human prostate cancer. 1216 93

Evasion of cellular senescence is required for the immortal phenotype of tumor cells. The tumor suppressor genes p16(INK4A), pRb, and p53 have been implicated in the induction of cellular senescence. To identify additional genes and pathways involved in the regulation of senescence in prostate epithelial cells (PrECs), we performed serial analysis of gene expression (SAGE). The gene expression pattern of human PrECs arrested because of senescence was compared with the pattern of early passage cells arrested because of confluence. A total of 144,137 SAGE tags representing 25,645 unique mRNA species was collected and analyzed: 157 mRNAs (70 with known function) were up-regulated and 116 (65 with known function) were down-regulated significantly in senescent PrECs (P < 0.05; fold difference >2.5). The differential regulation of an exemplary set of genes during senescence was confirmed by quantitative real-time PCR in PrECs derived from three different donors. The results presented here provide the molecular basis of the characteristic changes in morphology and proliferation observed in senescent PrECs. Furthermore, the differentially expressed genes identified in this report will be instrumental in the further analysis of cellular senescence in PrECs and may lead to the identification of tumor suppressor genes and proto-oncogenes involved in the development of prostate cancer.
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PMID:Characterization of epithelial senescence by serial analysis of gene expression: identification of genes potentially involved in prostate cancer. 1241 55

Deregulated proliferation is one of the main events in neoplastic transformation, and this has prompted increased attention being given to the understanding of the mechanisms involved in cell cycle regulation and its alterations. The 'retinoblastoma pathway', a key effector controlling G1-S phase transition, includes several oncogenes and tumour suppressor genes which display a wide range of abnormalities with potential usefulness as markers of evolution or treatment response in prostate cancer. Among these, the existence of p53 mutations seems to predict resistance to radiotherapy or systemic treatment, and p16 overexpression or p27 downregulation seems to serve as markers of poor evolution. The well-established existence of a critical hormonal role in prostate carcinogenesis coupled with the relationship of androgenic activity and regulation of several cell cycle modulators forces cell cycle control in the prostate to be envisioned as a highly complex steroid-influenced system, which will undoubtedly have critical implications in the future management of prostate cancer patients.
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PMID:Alterations of cell cycle-regulatory genes in prostate cancer. 1241 86

Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, is a promising chemopreventive agent. We recently showed that green tea polyphenols exert remarkable preventive effects against prostate cancer in a mouse model and many of these effects are mediated by the ability of polyphenols to induce apoptosis in cancer cells [Proc. Natl. Acad. Sci. USA 98 (2001) 10350]. Earlier, we showed that EGCG causes a G0/G1 phase cell cycle arrest and apoptosis of both androgen-sensitive LNCaP and androgen-insensitive DU145 human prostate carcinoma cells, irrespective of p53 status [Toxicol. Appl. Pharmacol. 164 (2000) 82]. Here, we provide molecular understanding of this effect. We tested a hypothesis that EGCG-mediated cell cycle dysregulation and apoptosis is mediated via modulation of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery. As shown by immunoblot analysis, EGCG treatment of LNCaP and DU145 cells resulted in significant dose- and time-dependent (i) upregulation of the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18, (ii) down-modulation of the protein expression of cyclin D1, cyclin E, cdk2, cdk4, and cdk6, but not of cyclin D2, (iii) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27, and (iv) decrease in the binding of cyclin E toward cdk2. Taken together, our results suggest that EGCG causes an induction of G1 phase ckis, which inhibits the cyclin-cdk complexes operative in the G0/G1 phase of the cell cycle, thereby causing an arrest, which may be an irreversible process ultimately leading to apoptotic cell death. This is the first systematic study showing the involvement of each component of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest and apoptosis of human prostate carcinoma cells by EGCG.
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PMID:Molecular pathway for (-)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells. 1255 91

Dose-escalated conformal radiotherapy is increasingly being used to radically treat prostate cancer with encouraging results and minimal long-term toxicity, yet little is known regarding the response of normal or malignant prostate cells to ionizing radiation (IR). To clarify the basis for cell killing during prostate cancer radiotherapy, we determined the IR-induced expression of several apoptotic- (bax, bcl-2, survivin and PARP) and G1-cell cycle checkpoint- (p53 and p21(WAF1/Cip1)) related proteins, in both normal (PrEC-epithelial and PrSC-stromal) and malignant (LNCaP, DU-145 and PC-3; all epithelial) prostate cells. For these experiments, we chose doses ranging from 2 to 10 Gy, to be representative of the 1.8-2 Gy daily clinical fractions given during curative radiotherapy and the 8-10 Gy single doses given in palliative radiotherapy. We observed that IR-induced bax and p21(WAF1/Cip1) protein expression were attenuated selectively in normal stromal and epithelial cell cultures, yet maintained their p53-dependency in malignant cell lines. For each cell culture, we also determined total apoptotic and overall radiation cell kill using a short-term nuclear morphologic assay and a long-term clonogenic survival assay, respectively. Clonogenic survival, as measured by the surviving fraction at 2 Gy (SF2), ranged from 0.05 (PrEC) to 0.55 (DU-145), suggesting that malignant prostate cells are more radioresistant than normal prostate cells, for this series. IR-induced apoptotic cell kill was minimal (less than 6% cell after a dose of 10 Gy at times of 24-96 h) and was not dose-dependent. Furthermore, apoptotic kill was not correlated with either molecular apoptotic response or clonogenic cell kill. Using a flow cytometric proliferation assay with the PrSC (stromal) and DU-145 (epithelial) representative cultures, we observed that a senescent-like phenotype (SLP) emerges within a sub-population of cells post-irradiation that is non-clonogenic. Terminal growth arrest was dose-responsive at 96 h following irradiation and associated with long-term expression of both p21(WAF1/Cip1) and p16(INK4a) genes. Future strategies for prostate radiotherapy prediction or novel treatments should additionally focus on terminal growth arrest as an important endpoint in prostate cancer therapy.
Prostate Cancer Prostatic Dis 2003
PMID:Cell death in irradiated prostate epithelial cells: role of apoptotic and clonogenic cell kill. 1266 70

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


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