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)

We are interested in studying the possibility of modulating prostatic cell growth by manipulating apoptosis. Here we show that 1 microM staurosporine (STS) induces a human androgen-independent prostatic tumor cell line, DU145, to undergo dramatic changes in morphology and results in programmed cell death. Several genes involved in apoptosis were analyzed for expression in STS-treated and untreated DU145 cells. It was observed that these genes were differentially regulated. The expression level of bcl-2, bcl-xL, Ich-1L remains unchanged in treated and untreated cells. On the other hand, DAD1 and interleukin-1 beta-converting enzyme (ICE) were downregulated while bcl-xs and Ich-1s were upregulated. By blocking bcl-2 gene expression using antisense oligonucleotides, it was determined that the anti-bcl-2 oligonucleotides have no effect on the proliferation of DU145 or STS-treated DU145 cells. These results demonstrate that programmed cell death can be induced in an androgen-independent prostatic cancer cell line and BCL-2 was found not to play an important role in preventing STS-induced apoptosis in the DU145 cell line.
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PMID:Induction of apoptosis in prostatic tumor cell line DU145 by staurosporine, a potent inhibitor of protein kinases. 870 Aug 2

Beta-carotene, canthaxanthin and retinoic acid (RA) inhibited growth of human DU145 prostate cancer cells by 45, 56 and 18%, respectively. Lycopene was also found to inhibit cell growth. Other carotenoids including xanthophyll (lutein), cryptoxanthin and zeaxanthin were less effective. Liarozole (a novel imidazole-derived inhibitor of intracellular RA catabolism) had a modest effect upon cell growth, this drug significantly amplified the pro-apoptotic actions of beta-carotene and RA. RA-induced expression of thymosin beta-10, an apoptotic accelerant, was associated with increased nuclear DNA nicking as measured using TUNEL. Liarozole enhanced the proapoptotic actions of RA upon DNA fragmentation in a dose-dependent manner. These actions were accompanied by inhibition of the cell survival factor bcl-2. Liarozole may thus prove useful as a novel chemotherapeutic/chemopreventive agent by boosting retinoid-induced apoptosis in the prostate.
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PMID:Liarozole amplifies retinoid-induced apoptosis in human prostate cancer cells. 879 6

Seventy-seven men with histologically proven and newly diagnosed prostate cancer we investigated for the presence of bcl-2 protein overexpression and p53 protein accumulation 1 immunohistochemistry. Forty-five men had evidence of locally advanced and metastatic disease and we treated by means of hormone manipulation. Twenty-eight patients either failed to respond to initial hormone manipulation or relapsed within 37 months from diagnosis (median 20 months). Of the 77 cancers, 37 (48% showed bcl-2 overexpression at diagnosis. Twenty-seven of those were treated with androgen ablation and 2 (74%) had hormone-refractory disease (P = 0.0128). Twenty-three of 77 men (29.8%) had nuclear staining for p53 protein. Twenty-one of those were treated with hormone manipulation and 14 (66.6%) showed hormone resistance (P = 0.0012). Seventeen patients had both bcl-2 overexpression and p53 protein accumulation, 16 of whom were hormonally treated, with 13 (81.2%) having hormone-refractory disease (P < 0.0001). These findings suggest that the combined detection of p53 protein accumulation and bcl-2 overexpression may be useful in predicting hormone resistance in prostate cancer. By deregulating programmed cell death, alteration in these genes may prevent patients from responding to androgen ablation, or allow them to escape hormonal control of the disease.
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PMID:bcl-2 overexpression combined with p53 protein accumulation correlates with hormone-refractory prostate cancer. 888 14

The incidence of programmed cell death (apoptosis) and cell proliferation was investigated in the normal and malignant human prostate to define the significance of their potential deregulation in human prostate cancer. The incidence of "spontaneous" apoptosis was analyzed using an in situ end-labeling procedure for detection of nucleosomal DNA fragmentation, as well as the pattern and topological localization of expression of the 2 proteins regulating apoptosis, TGF-beta1, and bcl-2, in 40 primary prostatic adenocarcinomas with varying tumor grades, 17 lymph nodes positive for metastatic prostate cancer and 9 normal prostate specimens. The basal level of cell proliferation of the different prostatic cell populations in the same specimens was determined, utilizing the Ki-67 nuclear antigen. Localized prostate cancer cells exhibited a relatively low rate of apoptosis, which was significantly lower than the apoptotic index of normal prostate glandular epithelial cells. Metastatic prostate tumor cells, however, exhibited a significantly higher apoptotic index compared with localized prostate cancer cells. A significant increase in the proliferative index was detected in prostatic tumors compared with the normal gland (5-fold), and there was an even more marked elevation in the proliferative index of the metastatic prostate tumor cells compared to the normal prostate epithelial cells (approximately 24-fold). Immunohistochemical analysis of normal and malignant prostate specimens revealed a predominant TGF-beta immunoreactivity in the glandular epithelial cells, while the stromal component was totally negative. There was a significant increase in the levels of TGF-beta in primary prostatic tumors compared to the normal prostate. Bcl-2 expression was detected among certain populations of tumor epithelial cells in a mutually exclusive topological distribution pattern for apoptosis. In marked contrast, neither TGF-beta1 nor bcl-2 immunoreactivity was detected in metastatic prostate tumor cells, despite their high proliferative and apoptotic rates. Balancing the prostatic growth equation for the prostatic tumor epithelial cell populations revealed a substantial net increase in cell number in both primary and metastatic prostate cancers. This loss of apoptotic control in favor of cell proliferation may be responsible for prostate cancer initiation and progression.
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PMID:Incidence of apoptosis and cell proliferation in prostate cancer: relationship with TGF-beta1 and bcl-2 expression. 890 Mar 67

Several oncogenes involved in prostate carcinogenesis activate mitogen-activated protein (MAP) kinases, which can relay both proliferative (via extracellular regulated kinases (ERK)) and apoptotic signals (via jun N-terminal protein kinases (JNK)) to the nucleus. Mitogen-activated protein kinase phosphatase 1 (MKP-1) is induced by several oncogenes in the ras-dependent pathway and can inactivate both MAP kinase pathways. The role of MKP-1 in proliferation and apoptosis is, however, still controversial. A series of 51 prostate cancers, including a subset (n = 13) that had been previously treated by androgen ablation, was used to examine whether MKP-1 mRNA and protein expression correlated with that of ERK-1, JNK-1, bcl-2, which confers resistance to apoptosis, and apoptotic index measured by in situ end-labeling of fragmented DNA. In a subset of tumors, MKP-1 expression was assessed by semiquantitative RT-PCR and was compared with both ERK-1 and JNK-1 enzymatic activity. In cases not treated by androgen ablation, MKP-1 was overexpressed in the preinvasive stage of prostate cancer, but its expression decreased with higher histologic grade and advanced disease stage. There was coexpression of MKP-1, ERK-1, and JNK-1 proteins. In addition, MKP-1 expression was inversely correlated to JNK-1 but not to ERK-1 enzymatic activity. Finally, MKP-1 and bcl-2 were inversely related to apoptotic indices. In cases treated by total androgen ablation, MKP-1 and bcl-2 were both down-regulated, whereas JNK-1 was up-regulated. Subpopulations of cells that did not undergo apoptosis maintained expression of both MKP-1 and bcl-2. These results suggest that MKP-1 overexpression is associated with the early phases of neoplastic transformation in prostate tissue. The enzymatic data on MKP-1 kinase substrates and the inverse correlation between MKP-1 and parameters of programmed cell death support the hypothesis that MKP-1 inhibits apoptosis in human prostate tumors, perhaps through the JNK pathway.
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PMID:Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. 901 Apr 48

In this study we evaluated the effect of over-expression of the bcl-2 gene, a potent apoptosis suppressor, on radiation-induced apoptotic cell death in 2 human prostate cancer cell lines, androgen-independent PC-3 cells and androgen-sensitive LNCaP cells. Cells were transfected with the bcl-2 gene and bcl-2 transfectant clones isolated under neomycin selection; bcl-2 gene integration and level of mRNA and protein expression in the cloned transfectants were examined by Southern, Northern and Western blot analyses, respectively. Parental, neo control and bcl-2-expressing cells were exposed to single or fractionated doses of ionizing irradiation, and the cellular response to radiation was determined at 24, 48 and 72 hr post-irradiation, on the basis of: (i) loss of cell viability, (ii) clonogenic survival and (iii) induction of apoptotic DNA fragmentation. At 24 hr post-irradiation all cell lines, i.e., parental and bcl-2 transfectants, failed to form colonies, though the majority of bcl-2-expressing cells did not exhibit apoptotic morphology; bcl-2 over-expression in both cell lines reduced apoptosis 48 hr post-irradiation from 20-25% to 5% at a dose of 2,000 cGy. By 72 hr, bcl-2 over-expression afforded a 3-fold protection from radiation-induced apoptosis. There was no significant difference, however, in the clonogenic survival of the parental and bcl-2-expressing cells. Furthermore, there was a 24 hr delay in induction of the apoptosis marker gene SGP-2/TRPM-2 in the bcl-2-expressing cells, co-incidental with the delay in apoptotic DNA fragmentation.
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PMID:bcl-2 over-expression delays radiation-induced apoptosis without affecting the clonogenic survival of human prostate cancer cells. 903 38

We previously reported that a transgenic mouse line containing the fetal globin promoter linked to the SV40 T antigen (T Ag) viral oncogene (Ggamma/T-15) resulted in prostate tumors. In this study, we further explored tumor origin, frequency, invasiveness, androgen sensitivity, and gene expression pattern. T Ag was detected in adult but not fetal and neonatal prostates, suggesting a role for androgens in tumor progression. However, castration shortly after prostate morphogenesis did not prevent tumor development, suggesting an androgen-independent phenotype. Tumors originated within ventral or dorsal prostate lobes and involved intraepithelial neoplasia, rapid growth in the pelvic region, and metastasis to lymph nodes and distant sites. In addition, the primary cancers could be propagated in nude mice or nontransgenic mice. Seventy-five percent of hemizygous and 100% of homozygous transgenic males developed prostate tumors, suggesting a T Ag dosage effect. Biochemical characterization of advanced tumors revealed markers of both neuroendocrine and epithelial phenotypes; markers of terminal differentiation are lost early in tumorigenesis. Tumor suppressor genes (p53 and Rb), normally bound to T Ag, were up-regulated; bcl-2 proto-oncogene, which prevents apoptosis, was slightly up-regulated. Myc, a stimulus to cell cycle progression, was unchanged. We propose the Ggamma/T-15 transgenic line as a model of highly aggressive androgen-independent metastatic prostate carcinoma with features similar to end-stage prostate cancer in humans.
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PMID:Prostate cancer progression, metastasis, and gene expression in transgenic mice. 904 Nov 92

Although the role of bcl-2 in apoptosis has been described, its involvement in prostate cancer (CAP) progression is less well understood, but thought to be involved with the transition of CAP from androgen-sensitivity to androgen-independence, where its expression is augmented following androgen ablation. For treating these recurrent androgen-independent tumors, following hormone treatment failure, a new tier of therapy based upon growth factor deprivation has been suggested, implemented by antisense oligonucleotides (oligos) directed against mRNA encoding a critical growth regulatory autocrine loop (comprised of transforming growth factor-alpha (TGF-alpha) and its binding site, the epidermal growth factor receptor (EGFR). To determine whether oligo-induced growth factor deprivation therapy similarly enhanced expression of bcl-2 (as follows androgen deprivation) human prostate cancer derived PC-3 cells were treated in vitro with oligos directed against TGF-alpha (MR-1) and/or EGFR (MR-2). After 5 days of treatment cells were immunochemically stained for human bcl-2. In similar experiments, cells were treated for 3 days prior to extraction of proteins, Western blot analysis, photography and computer evaluation of protein density by SigmaScan software. Immunostained cells treated with oligos directed against mRNA encoding TGF-alpha (MR-1) either alone or in combination with that directed against EGFR (MR-2) had increased bcl-2 expression (+3 to +5). In addition, the intensity of Western blots scanned for bcl-2 expression were 19%, 32% and 30% greater in cells treated with oligos directed against TGF-alpha, EGFR or their combination, respectively. We conclude that enhanced bcl-2 expression followed antisense oligo induced growth factor deprivation. This result is similar to that found upon androgen deprivation therapy, and also demonstrates additional biologic activity of this new class of molecular therapeutic agents.
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PMID:Enhanced expression of bcl-2 following antisense oligonucleotide mediated growth factor deprivation. 923 7

The clinical course of prostate cancer (PCa), the most common cancer in Swedish men, is highly variable and difficult to predict. Consequently, there is an urgent need to distinguish tumours with a high risk of progression from those with a low risk. To investigate the prognostic implications of proliferation and apoptosis, two important processes in tumor biology, immunoreactivity for biomarkers associated with these processes was assessed, quantified in indexes, and related to cause-specific survival (CSS). A consecutive series of 186 men presenting with voiding symptoms and PCa were treated with transurethral resection and deferred endocrine therapy. After 13-21 years follow-up, 43% of these men had died of prostate cancer. In a subgroup of men with localised disease at the time of diagnosis, 27% succumbed to the disease. Immunoreactivity for p53 protein, indicative of a defective p53 function, predicted shorter CSS in univariate (52 vs 123 months, p < 0.0001), but not in multivariate analysis. Mean index for the apoptosis blocking bcl-2 protein was higher in foci of prostatic intraepithelial neoplasia, a putative precursor to PCa, than in manifest cancer areas (79 vs 12, p < 0.0001). This indicates that bcl-2 may be involved in early tumourigenesis. No prognostic value was found for the bcl-2 index. A high index for the proliferation marker Ki-67 predicted shorter CSS in univariate (53 vs 132 months p < 0.0001) and in multivariate analysis. To test if p53 is predictive for clinical radioresistance, as suggested by experimental models, p53 immunoreactivity was investigated in biopsies obtained before radical radiotherapy in an unrelated series of 60 PCa patients. Patients with p53 reactive tumours had longer CSS, indicating that p53 is not treatment-predictive for radiotherapy in Pca. Core biopsies were obtained before and a week after castration therapy in patients with advanced PCa. According to the serum prostate specific antigen (PSA) level 3 months after therapy, 15 responding tumours and 13 non-responding tumours were selected. Regressive morphology was seen in 14/15 responders after castration therapy, compared with 4/13 non-responders. Median apoptotic index increased significantly after castration therapy for responders (from 2.6 to 3.5, p < 0.05) whereas it was 2.8 before and after therapy in non-responders. This indicates that subsequent clinical response can be predicted by the induction of regressive morphology and an increase in apoptotic index. In conclusion, immunoreactivity for Ki-67 appeared to be a putative prognostic factor in PCa, whereas the prognostic value of p53 and bcl-2 was dubious. p53 immunoreactivity did not appear to be predictive of radioresistance in PCa. Cellular response in biopsies shortly after castration therapy might be treatment-predictive.
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PMID:Prognostic factors in prostate cancer. 924 5

A role has been delineated for both bcl-2 and NF-kappa B in mediating an adaptive survival response to the TNF-alpha signaling pathway for apoptosis. Additionally, we and others have demonstrated a role for bcl-2 upregulation during progression of prostate cancer and acquisition of androgen-independent growth (T. J. McDonnell et al., 1992, Cancer Res. 52, 6940-6944). Therefore, the relationship between bcl-2 and NF-kappa B in regulating TNF-alpha-induced apoptosis was investigated in prostate carcinoma cells. Enforced overexpression of bcl-2 protein in prostatic carcinoma cells impaired TNF-alpha-mediated cytotoxicity. Expression of bcl-2 did not impose a block to, or potentiate, TNF-alpha signaling of I kappa B alpha degradation, nuclear import of the RelA p65, or NF-kappa B-dependent transactivation. Expression of two dominant-negative I kappa B alpha mutant proteins significantly enhanced TNF-alpha-induced apoptosis in control cells but not in cells expressing high levels of bcl-2 protein. Similarly, PDTC, a strong antioxidant that interferes with activation of NF-kappa B in these prostate carcinoma cells, also potentiated TNF-alpha-stimulated apoptosis signaling through a bcl-2-regulated mechanism. These findings indicate that modulation of NF-kappa B survival signaling may be used to clinical advantage in the treatment of prostate cancer patients. The efficacy of strategies proposed to enhance TNF-alpha-mediated cytotoxicity by inhibiting NF-kappa B will likely be influenced by context-dependent variables such as bcl-2 expression.
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PMID:Bcl-2 suppresses apoptosis resulting from disruption of the NF-kappa B survival pathway. 941 72


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