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)

Loss of heterozygosity (LOH) involving the long arm of chromosome 13 has been reported to occur in as many as one third of primary prostate cancers. Candidate tumor suppressor genes on 13q that may be important in the development of prostate cancer include the retinoblastoma susceptibility gene (RBI) and a gene associated with inherited breast cancer (BRCA2). To define the pattern of allelic loss of 13q in prostate cancer, LOH analysis was performed using nine mapped polymorphic markers spanning the entire chromosomal arm. Nineteen (48%) of 40 prostate cancer cases obtained following radical prostatectomy demonstrated atllelic loss with at least one marker. Furthermore, 13 (33%) of 40 cases had evidence of allelic loss involving a region of 13q14 containing RB1. To test the hypothesis that RB1 is the targeted tumor suppressor gene in this region, 37 of 40 cases were assessed for expression of pRB, the protein product of RB1 using immunohistochemical techniques. By this analysis, 8 (22%) of 37 prostate tumors demonstrated no pRB expression. However, allelic loss at RB1, assessed with an intragenic marker, did not correlate with absent pRB expression (Fisher's exact test, P=0.375). Taken together, these data confirm that allelic loss of a common region of 13q14 occurs in approximately one third of prostate cancers. Lack of correlation of LOH at RB1 with absent pRB expression suggests the existence of another tumor suppressor gene in this region important in prostate cancer.
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PMID:Distinct regions of allelic loss on 13q in prostate cancer. 864 Jul 74

Autocrine production of transforming growth factor alpha and overexpression of the epidermal growth factor receptor (EGFR) may contribute to androgen-independent prostatic cancer growth at both primary and metastatic sites. Previously, we showed that human EGFR-blocking monoclonal antibody mAb225 inhibited the growth of DU145 human prostatic cancer cells. Here we explore the hypothesis that mAb225 may act by interfering with cell cycle traversal in these cells. Treatment with mAb225 induced G1 arrest, which was accompanied by a marked decrease in CDK2-, cyclin A-, and cyclin E-associated histone H1 kinase activities, and a sustained increase in cell cycle inhibitor p27KIP1. The increased p27KIP1 levels were attributable to elevation of both transcription and translation. CDK2 associated with p27KIP1 was increased in mAb225-treated DU145 cells. The retinoblastoma-related protein p130 remained hypophosphorylated in these retinoblastoma-negative cells. These studies demonstrate that the antiproliferative effect of EGFR blockade in DU145 cells may be mediated by up-regulation of p27KIP1 at both the mRNA and protein levels.
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PMID:Anti-epidermal growth factor receptor monoclonal antibody 225 up-regulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145. 870 5

The cyclin D/cyclin-dependent kinase (CDK)/CDK-inhibitory proteins/retinoblastoma protein (pRb) pathway is hypothesized to control the G1-S check point. The role of this pathway is reported to be different depending on the status of pRb. In the present study, we examined nine human urological tumor cell lines. Cells lacking functional pRb expressed p16, instead of forming cyclin D/ CDK4 complex. In the LNCaP prostatic cancer cell line, however, both p16/CDK4 and cyclin D/ CDK4 complexes were present independently, probably because of partial loss of pRb. In view of the concomitant presence of the incompatible complexes, LNCaP should provide us with a valuable model for the study of this pathway in cancer cells.
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PMID:Concomitant presence of p16/cyclin-dependent kinase 4 and cyclin D/cyclin-dependent kinase 4 complexes in LNCaP prostatic cancer cell line. 914 Jan 5

The science of cancer is being revolutionized by the collaboration of cancer-afflicted families and determined scientists. The result has been an explosion of knowledge about inherited susceptibilities to particular types of cancer and the possibilities of testing for those susceptibilities. Susceptibility tests are becoming available for breast cancer, ovarian cancer, prostate cancer, colon cancer, retinoblastoma, and hereditary medullary thyroid cancer--cancers both common and rare. Now, cancer patients, cancer families, and cancer physicians face the challenge of determining how--and whether--such tests can be put to good use.
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PMID:Genetic testing for cancer susceptibility: challenges for creators of practice guidelines. 968 74

1Alpha,25-dihydroxyvitamin D3 (1,25 D), the most active metabolite of vitamin D3, exerts antiproliferative and prodifferentiating effects on some human prostate cancer cell lines. We previously reported an inverse relationship between functional vitamin D receptor (VDR) levels and antiproliferative response to 1,25 D in two human prostate cancer cell lines, LNCaP and ALVA 31. Although LNCaP cells are far more sensitive to growth inhibition by 1,25 D than ALVA 31 cells, LNCaP express approximately half the number of VDR as ALVA 31. Two other human prostate cancer cell lines studied, PC3 and DU145, express lower levels of functional VDR and are relatively insensitive to growth inhibition by 1,25 D. In this report, we investigated potential mechanisms of the variable antiproliferative activity of 1,25 D. In PC3 cells stably expressing VDR [PC3(VDR)] at levels comparable to LNCaP, 1,25 D treatment resulted in only moderate growth inhibition. These results further support the contention that VDR expression, although required, is not sufficient for maximal growth suppression by 1,25 D, as is exhibited by LNCaP cells. We did not detect 1,25 D-mediated DNA fragmentation after 4 days of 1,25 D treatment in either LNCaP or ALVA 31 cells. This result suggests that variability in 1,25 D sensitivity does not derive from differences in the capacity of these cells to undergo apoptosis in response to 1,25 D. Flow cytometry of propidium iodine-stained cells revealed that 48 h 1,25 D treatment of LNCaP cells resulted in a 2-fold decrease of cells in G2/M plus S phases and accumulation of LNCaP cells in the G1/G0 phase. This effect persisted for 72 h after 1,25 D removal. In contrast, 1,25 D did not significantly alter the cell cycle distribution of ALVA 31 or PC3(VDR) cells. Consistent with accumulation of cells in G1/G0, 1,25 D treatment of LNCaP cells resulted in decreased retinoblastoma protein phosphorylation, repressed E2F transcriptional activity, increased levels of the cyclin-dependent kinase (CDK) inhibitor p21(WAF1, CIP1), and decreased CDK2 activity. However, p21 messenger RNA levels were not altered, suggesting translational or posttranslational regulation of p21 by 1,25 D. In contrast, p21 was not detected in ALVA 31 or PC3(VDR) and was not induced by 1,25 D, consistent with the failure of 1,25 D to influence cell cycle distribution in these cells. These results suggest that variability in sensitivity to the antiproliferative effects of 1,25 D among prostate cancer cells is dependent, at least in part, on the integrity of the retinoblastoma pathway and in particular on p21 expression and 1,25 D regulation of CDK2 activity.
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PMID:Antiproliferative effect of 1alpha,25-dihydroxyvitamin D3 in human prostate cancer cell line LNCaP involves reduction of cyclin-dependent kinase 2 activity and persistent G1 accumulation. 949 54

The molecular mechanism of androgen-independent growth of prostate cancer after androgen ablation was explored in LNCaP cells. An androgen-dependent clonal subline of the LNCaP human prostate carcinoma cell line, LNCaP 104-S, progressed to a slow growing stage (104-R1) and then to a faster growing stage (104-R2) during more than 2 yr of continuous culture in the absence of androgen. Androgen-induced proliferation of 104-S cells is inhibited by the antiandrogen Casodex, while proliferation of 104-R1 and 104-R2 cells is unaffected by Casodex. This indicates that proliferation of 104-R1 and 104-R2 cells is not supported by low levels of androgen in the culture medium. Compared with LNCaP 104-S cells, both 104-R1 and 104-R2 cells express higher basal levels of androgen receptor (AR), and proliferation of these two cell lines is paradoxically repressed by androgen. After continuous passage in androgen-containing medium, 104-R1 cells reverted back to an androgen-dependent phenotype. The mechanism of androgenic repression of 104-R1 and 104-R2 sublines was further evaluated by examining the role of critical regulatory factors involved in the control of cell cycle progression. At concentrations that repressed growth, androgen transiently induced the expression of the cyclin-dependent kinase (cdk) inhibitor p21waf1/cip1 in 104-R1 cells, while expression of the cdk inhibitor p27Kip1 was persistently induced by androgen in both 104-R1 and 104-R2 cells. Induced expression of murine p27Kip1 in 104-R2 cells resulted in G1 arrest. Specific immunoprecipitates of Cdk2 but not Cdk4 from androgen-treated 104-R1 cells contained both p21waf1/cip1 and p27Kip1. This observation was confirmed by in vitro assay of histone H1 and Rb (retinoblastoma protein) phosphorylation by the proteins associated with the immune complex. Furthermore, inhibition of Cdk2 activity correlated with the accumulation of p27Kip1 and not p21waf1/cip1. From these results we conclude that androgenic repression of LNCaP 104-R1 and 104-R2 cell proliferation is due to the induction of p27Kip1, which in turn inhibits Cdk2, a factor critical for cell cycle progression and proliferation.
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PMID:Progression of LNCaP prostate tumor cells during androgen deprivation: hormone-independent growth, repression of proliferation by androgen, and role for p27Kip1 in androgen-induced cell cycle arrest. 965 99

The role of the retinoblastoma gene product, RB, in transmitting the signals of apoptosis is unclear, but RB is considered to be antiapoptotic because RB mediates cell cycle arrest that also can interrupt intracellular signaling pathways leading to apoptosis. Gamma-radiation can cause apoptosis, the process of programmed cell death, via several mechanisms including DNA damage, ceramide production, and the generation of free radical oxygen species. We investigated the effect of RB on radiation-induced apoptosis by restoring normal RB expression in DU-145 prostate cancer cells that have one deleted and one truncated RB gene. DU-145 cells are highly resistant to apoptosis induced either by radiation or by the addition of ceramide. Two independently derived RB-positive DU-145 derivative cell lines underwent apoptosis after irradiation or exposure to the cell permeable C2-ceramide. Apoptosis in the RB-positive cell lines was not associated with major changes in the cell cycle response to irradiation. RB-mediated apoptosis occurred in the absence of expression of caspases 8, 6, 3, and 7 and without detectable cleavage of poly(ADP)ribose polymerase. However, a specific inhibitor of serine proteases, Na-p-Tosyl-L-lysyl-chloromethyl ketone, inhibited radiation-induced apoptosis in DU-145 cells expressing RB. Radiation-induced apoptosis was preceded by an increase in JUN protein expression and accompanied by activation of the stress-related JUN kinase. Our data show that RB is proapoptotic in DU-145 cells and acts upstream of JUN expression and JNK activation.
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PMID:Radiation-induced apoptosis mediated by retinoblastoma protein. 969 55

To clarify the role in prostate tumorigenesis played by loss of the three known or putative tumor suppressor loci on the centromeric portion of chromosome 13q, we examined 80 clinically localized and 15 advanced prostate carcinomas for allelic loss at microsatellite markers mapped to this region, including markers tightly linked to the BRCA-2, retinoblastoma (Rb), and DBM (deleted in B-cell malignancy) loci. Among the 80 clinically localized cases, 24 showed allelic loss at one or more 13q loci. In all cases with loss, the Rb and/or DBM loci were lost. No cases were found with loss of Rb without loss of DBM or loss of DBM without loss of Rb, implying a role for both the Rb and DBM loci in clinically localized prostate cancer. Loss of the BRCA-2 locus was less common (4 of 55 informative cases) and was always associated with loss of Rb and/or DBM loci. Thus, the BRCA-2 locus does not appear to play as important a role in clinically localized prostate cancer as the Rb and/or DBM loci. Allelic loss on 13q was extremely common in the clinically advanced cases; it was present in 14 of the 15 cases. The rate of allelic loss at each of the three tumor suppressor loci was increased significantly in the advanced cases (P < 0.01, Fisher's exact test). Thus, loss of heterozygosity on 13q is very common in prostate cancer and occurs at all three known or putative tumor suppressor loci on the centromeric portion of chromosome 13q.
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PMID:Allelic loss on chromosome 13q in human prostate carcinoma. 981 75

Previous studies have shown that rapid cell proliferation is associated with elevated glucose consumption. However, those studies did not establish whether glucose is required for prostate cancer cell proliferation or define the molecular mechanisms by which glucose regulates cell division. We addressed these issues by studying two metastatic human prostate cancer cell lines: DU145, which is androgen independent and highly proliferative; and LNCaP, which is androgen dependent and relatively slow growing. We found that proliferation of DU145 cells was significantly inhibited by reduction of glucose in the medium to 0.5 g/L, which is half the physiologic concentration, whereas LNCaP cells grew at control rates even in the presence of only 0.05 g/L glucose. Glucose deprivation of DU145 cells caused a 90% reduction in DNA synthesis; a 10-20-fold reduction in cyclins D and E and CDK4 levels; and cell cycle arrest in G0-G1. However, glucose deprivation did not cause global inhibition of protein synthesis, since mutant p53 levels increased in glucose-deprived DU145 cells. This observed increase in mutant p53 levels was not associated with a rise in p21 levels. Glucose deprivation of DU145 cells also led to apparent dephosphorylation of mutant retinoblastoma (RB) protein. We conclude that: 1) high levels of glucose consumption are required for rapid proliferation of androgen-independent prostate cancer cells, 2) glucose may not be required for slow growth of androgen-dependent prostate cancer cells, and 3) glucose promotes passage of cells through early G1 by increasing the expression of several key cell cycle regulatory proteins that normally inhibit RB function.
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PMID:Regulation of prostate cancer cell division by glucose. 1043 Jan 83

The cell cycle is governed by cyclin dependent kinases (cdks), which are activated by binding of cyclins, inhibited by cdk inhibitors and regulated by phosphorylation and dephosphorylation. Exposure to high dose dihydrotestosterone (DHT) inhibits population growth of the human prostate carcinoma cell line, LNCaP. To determine the mechanism of growth arrest by high dose DHT, we assayed the changes in cell cycle profile and the cell cycle regulators that mediate these effects. Treatment of asynchronously growing LNCaP cells with 100 nM DHT caused a G1 arrest. The proportion of cells in S phase fell from 22 to 2%, while the G1 fraction rose from 74 to 92% by 24 h. Loss of phosphorylation of the retinoblastoma protein was noted and cdk4 and cyclin E/ cdk2 activities fell. Inhibition of these G1 cyclin dependent kinases was not due to loss of either cyclin or cdk proteins nor to increases in the cdk inhibitors p16INK4A and p21CiP1. p21Cip1 protein levels remained constant, and cyclin E-associated p21CiP1 fell, suggesting that p21CiP1 is not relevant to this form of cyclin E/cdk2 inhibition. Of note, total p27KiP1 levels and cyclin E-associated p27Kip1 increased as cells arrested and the amount of the CAK activated cdk2 bound to cyclin E decreased. p27KiP1 immunodepletion experiments demonstrated that the DHT-mediated increase in p27Kip1 was sufficient to fully saturate and inhibit target cyclin E/ cdk2. The inhibition of cyclin E/cdk2 by p27Kip1 contributes to G1 arrest of LNCaP following high dose DHT. p27KiP1 may be a key effector of androgen dependent growth modulation in prostate cancer cells.
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PMID:Involvement of p27Kip1 in G1 arrest by high dose 5 alpha-dihydrotestosterone in LNCaP human prostate cancer cells. 1069 12


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