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: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We treated primary epithelial cells from human normal prostate (NEPC) and prostate cancer (CEPC) with all-trans-retinoic acid (RA) to study whether it regulates the activity of tissue transglutaminase (tTGase), an enzyme that accumulates in cells undergoing apoptosis. tTGase activity was assessed by [14C]spermidine incorporation; tTGase, P53, Bcl-2, and p21 protein levels were evaluated by Western blotting; and RA receptors (RAR alpha, -beta, and -gamma), tTGase, retinol-binding protein (RBP), and cellular RBP type I transcripts were determined by semiquantitative RT-PCR. After 72-96 h of 10(-6) mol/L RA treatment, cell growth inhibition and apoptosis were associated with increased tTGase activity in both NEPC and CEPC, and with increased tTGase protein and messenger ribonucleic acid levels only in NEPC. Moreover, RA down-regulated RAR alpha and -beta and increased RBP messenger ribonucleic acid levels in NEPC, whereas it increased RAR beta gene expression and decreased Bcl-2 protein levels in CEPC. Our results suggest that RA induces tTGase gene expression and enzyme activity in normal prostate cells, and that RA-regulated pathways are impaired in cancer cells. Moreover, down-regulation of Bcl-2 protein and up-regulation of RAR beta suggest that retinoid may act on the genetic defect responsible for prostate cancer progression.
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PMID:Changes in tissue transglutaminase activity and expression during retinoic acid-induced growth arrest and apoptosis in primary cultures of human epithelial prostate cells. 1019 96

Androgen ablation-induced prostate cancer regression is transient and ends with the regrowth of androgen-independent (AI) tumors. To mimic this evolution in culture, we chronically deprived an androgen-dependent (AD) prostate cancer cell line (LNCaP) of androgen, generating an AI derivative which retained limited hormone proliferative responsiveness and a barely detectable prostate-specific antigen (PSA) mRNA level. While the cytokeratin 8 (CK8) level was low, the androgen receptor (AR) protein in AI cells was on average tenfold greater than in AD cells. When challenged for susceptibility to undergo apoptosis, the AI cells were more resistant than AD cells to all-trans retinoic acid (tRA) and two chemotherapeutic agents, Taxol and Adriamycin, requiring higher doses and longer periods of treatment to achieve similar effects. Compared to AD cells, the partially apoptosis-resistant AI cells expressed four times more Bcl-2 protein and undetectable levels of p21/WAF1. Induction of apoptosis by tRA in both cell types did not affect their expression but was preceded by the activation of Rb and a pronounced reduction of AR protein level. The kinetics of the Rb activation and AR downmodulation in both cell types matched their tRA sensitivity, suggesting that these events may be required for tRA-induced apoptosis. The results show that the apoptotic pathway in AI cells, although more difficult to induce, is not irrevocably lost and that targeted reduction of the AR protein level with retinoids in combination with androgen ablation therapy may prolong remissions in advanced prostate cancer patients.
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PMID:Activation of Rb and decline in androgen receptor protein precede retinoic acid-induced apoptosis in androgen-dependent LNCaP cells and their androgen-independent derivative. 1022 52

Prostate cancer (PC) is an escalating health burden in the western world. A large number of patients still present with extraprostatic (i.e., T3/T4, N0, M0/M1 or any T category and M1 disease or involved lymph nodes) and therefore incurable disease. Since the work of Huggins in 1940, there have been no major therapeutic advances and androgen ablation remains the best treatment option for extraprostatic androgen-responsive PC. Eighty to ninety percent of PC patients respond well to this form of treatment initially. After a median time of approximately 2 years, however, relapse to an androgen-independent (AI) state occurs, followed by death after a further median 6 months. Androgen ablation is rarely curative. The major molecular defect in extraprostatic and AI PC is the inability of PC cells to initiate apoptosis in response to a variety of stimuli, including different forms of androgen ablation and cytotoxic agents. The balance between cellular proliferation and cell death is regulated by multiple genes or families of genes through the cell cycle. The exact mechanisms governing this intricate and complex process are as yet not fully understood. One family of genes involved in cell survival/death control is the Bcl-2 gene family, which consists of homologous proteins that function to regulate distal and crucial commitment steps of the apoptotic pathway. The Bcl-2 family constitutes both agonists and antagonists of apoptosis that function at least in part through protein-protein interactions between various members of the family. The final outcome depends on the relative ratio of death agonists and antagonists. Bcl-2 expression has been closely associated with the AI phenotype of PC. Cytotoxic chemotherapy may be used as palliative therapy in AI PC but has not been found effective. Most chemotherapeutic cytotoxic agents induce apoptosis in cancer cells by direct and indirect action on the cell cycle. In vitro and in vivo studies have established that Bcl-2 expression confers an antiapoptotic activity against androgen withdrawal and cytotoxic chemotherapy. It thus offers a tempting potential target for therapeutic manipulations of PC.
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PMID:Role of the Bcl-2 gene family in prostate cancer progression and its implications for therapeutic intervention. 1022 6

Understanding the functional roles of the molecular alterations that are involved in the oncogenesis of prostate cancer, the second most frequent cause of cancer-related deaths among men in the United States is the focus of numerous investigations. To examine the possible significance of alterations associated with the tumor suppressor gene, MMAC/PTEN, in prostate carcinoma, the biological and biochemical effects of MMAC/PTEN expression were examined in LNCaP cells, which are devoid of a functional gene product. Acute expression of MMAC/PTEN via an adenoviral construct resulted in a dose-dependent and specific inhibition of Akt/PKB activation, consistent with the phosphatidylinositol phosphatase activity of MMAC/PTEN. MMAC/PTEN expression induced apoptosis in LNCaP cells, although to a lesser extent than that observed with p53 via an adenoviral construct. However, MMAC/PTEN expression produced a growth inhibition that was significantly greater than that achieved with p53. Overexpression of Bcl-2 in LNCaP cells blocked MMAC/PTEN- and p53-induced apoptosis but not the growth-suppressive effects of MMAC/ PTEN, suggesting that the growth regulatory effects of MMAC/PTEN involve multiple pathways. These studies further implicate the loss of MMAC/PTEN as a significant event in prostate cancer and suggest that reintroduction of MMAC/PTEN into deficient prostate cancer cells may have therapeutic implications.
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PMID:Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN. 1036 71

Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for hormone-refractory human prostate cancer intervention. We examined whether a flavonoid antioxidant silibinin (an active constituent of milk thistle) decreases PSA levels in hormone-refractory human prostate carcinoma LNCaP cells and whether this effect has biological relevance. Silibinin treatment of cells grown in serum resulted in a significant decrease in both intracellular and secreted forms of PSA concomitant with a highly significant to complete inhibition of cell growth via a G1 arrest in cell cycle progression. Treatment of cells grown in charcoal-stripped serum and 5alpha-dihydrotestosterone showed that the observed effects of silibinin are those involving androgen-stimulated PSA expression and cell growth. Silibinin-induced G1 arrest was associated with a marked decrease in the kinase activity of cyclin-dependent kinases (CDKs) and associated cyclins because of a highly significant decrease in cyclin D1, CDK4, and CDK6 levels and an induction of Cip1/p21 and Kip1/p27 followed by their increased binding with CDK2. Silibinin treatment of cells did not result in apoptosis and changes in p53 and bcl2, suggesting that the observed increase in Cip1/p21 is a p53-independent effect that does not lead to an apoptotic cell death pathway. Conversely, silibinin treatment resulted in a significant neuroendocrine differentiation of LNCaP cells as an alternative pathway after Cip1/p21 induction and G1 arrest. Together, these results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer.
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PMID:Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. 1037 42

The beclin 1 (BECN1) gene encodes a 60-kDa coiled-coil protein that interacts with the prototypic apoptosis inhibitor Bcl-2. Previous studies indicate that beclin 1 maps to a region approximately 150 kb centromeric to BRCA1 on chromosome 17q21 that is commonly deleted in breast, ovarian, and prostate cancer. The complete cDNA sequence of beclin 1 encodes a 2098-bp transcript, with a 120-bp 5' UTR, 1353-bp coding region, and 625-bp 3' UTR. Hybridization screening of a human genomic PAC library identified PAC 452O8, which contains the complete beclin 1 gene. Determination of the exon-intron structure of beclin 1 reveals 12 exons, ranging from 61 to 794 bp, which extend over 12 kb of the human genome. FISH analysis of human breast carcinoma cell lines using PAC 452O8 as probe identified allelic beclin 1 deletions in 9 of 22 cell lines. Sequencing of genomic DNA from 10 of these cell lines revealed no mutations in coding regions or splice junctions. Additionally, Northern blot analysis of 11 cell lines did not identify any abnormalities in beclin 1 transcripts. These results indicate that human breast carcinoma cell lines frequently contain allelic deletions of beclin 1, but not beclin 1 coding mutations.
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PMID:Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. 1039

Progression to androgen-independence remains the main obstacle to improving survival for patients with advanced prostate cancer. Although Bcl-2 expression in normal prostatic epithelial cells is low or absent, Bcl-2 is highly up-regulated in prostate cancer cells after androgen withdrawal and during progression to androgen-independence. Here, we test the efficacy of antisense Bcl-2 oligodeoxynucleotide (ODN) therapy administered adjuvantly after castration to delay time to androgen-independent recurrence in the androgen-dependent mouse Shionogi tumor model. Treatment of Shionogi tumor cells in vitro with antisense Bcl-2 ODN inhibited Bcl-2 expression in a dose-dependent and sequence-specific manner. Systemic administration of antisense Bcl-2 ODN in mice bearing Shionogi tumors beginning 1 day postcastration resulted in a more rapid regression of tumors and a significant delay of emergence of androgen-independent recurrent tumors. Furthermore, despite significant reduction of Bcl-2 expression in tumor tissues, antisense Bcl-2 ODN had no effect on Bcl-2 expression in normal mouse organs. These findings illustrate the potential utility of antisense Bcl-2 therapy for prostate cancer in an adjuvant setting with androgen ablation.
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PMID:Antisense Bcl-2 oligodeoxynucleotides inhibit progression to androgen-independence after castration in the Shionogi tumor model. 1046 3

The aim of this study was to obtain insight into the role of the multidrug resistance (MDR) phenomenon in hormone-independent progressive prostate cancer. Using immunocytochemistry and Western blotting we determined the expression of P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP), glutathione-S-transferase-pi (GST-pi), Bcl-2, Bax, topoisomerase (Topo) I, II alpha and II beta in the human prostate cancer cell lines PC3, TSU-Pr1, DU145 and LNCaP derivatives LNCaP-R, LNCaP-LNO and LNCaP-FGC. Proliferative activity was assessed by immunocytochemistry. MTT assays were used to determine the sensitivity to etoposide, doxorubicin and vinblastin. Pgp was not expressed in any of the cell lines. MRP was variably expressed. GST-pi was expressed in TSU-Pr1, PC3 and DU145. The expression of Bcl-2 was restricted to TSU-Pr1, whereas Bax was found in all cell lines. Topo II alpha was expressed at the highest level in the rapidly proliferating cell lines TSU-Pr1 and DU145. Topo I and II beta were equally expressed. Resistance profiles varied among the cell lines, with TSU-Pr1 being the most sensitive and LNCaP-LNO relatively resistant. Multiple MDR proteins were expressed in prostate cancer cell lines and may well influence response to chemotherapy. Future functional studies, using chemo-selected MDR models, may further help to determine the mechanism or combination of mechanisms underlying the resistance of prostate cancer to chemotherapy.
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PMID:Chemosensitivity of prostate cancer cell lines and expression of multidrug resistance-related proteins. 1049 44

Bcl-2 has emerged as a critical regulator of apoptosis in a variety of cell systems and is up-regulated during progression to androgen independence in prostate cancer cells. The objectives of this study were to characterize changes in Bcl-2 after androgen withdrawal and during progression to androgen independence in the human prostate LNCaP tumor model and determine whether adjuvant use of antisense Bcl-2 oligodeoxynucleotides (ODNs) with androgen ablation delays progression to androgen independence. Bcl-2 expression in LNCaP cells is down-regulated to undetectable levels by androgen in vitro and up-regulated after castration in vivo. Antisense Bcl-2 ODN treatment reduced LNCaP cell Bcl-2 messenger RNA and protein levels by >90% in a sequence-specific and dose-dependent manner at concentrations >50 nM. Bcl-2 mRNA levels returned to pretreatment levels by 48 h after discontinuing treatment. Athymic male mice bearing SQ LNCaP tumors were castrated and injected i.p. with 12.5 mg/kg/day with two-base mismatch ODN control, reverse polarity ODN control, or antisense Bcl-2 ODN. Tumor volume in control mice gradually increased 5-fold (range, 3-6) by 12 weeks after castration compared to a 10-50% decrease in precastrate tumor volume in mice treated with antisense Bcl-2 ODN. Changes in serum PSA paralleled changes in tumor volume, increasing 4-fold faster above nadir in controls than in mice treated with antisense Bcl-2 ODN. After decreasing 70% by 1 week after castration, PSA increased 1.6-fold above precastrate levels by 11 weeks in controls while staying 30% below precastrate levels in antisense-treated mice. In a second group of experiments, LNCaP tumor growth and serum PSA levels were 90% lower (P<0.01) in mice treated with antisense Bcl-2 ODN compared with mismatch or reverse polarity ODN controls. These results support the hypothesis that Bcl-2 helps mediate progression to androgen independence and is an appropriate target for antisense therapy.
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PMID:Progression to androgen independence is delayed by adjuvant treatment with antisense Bcl-2 oligodeoxynucleotides after castration in the LNCaP prostate tumor model. 1053 58

Bcl-2 expression is upregulated in prostate cancer cells after androgen withdrawal and is associated with the development of androgen independence and chemoresistance. Induction of apoptotic cell death after androgen ablation, or chemotherapy, may be enhanced through functional inhibition of bcl-2. In this report, we tested the effects of antisense bcl-2 oligodeoxynucleotides (ODN) with androgen ablation and taxane therapy on time to androgen-independent (Al) progression in the androgen-dependent Shionogi tumor model. Treatment of Shionogi tumor cells in vitro with 500 nmol/L antisense bcl-2 ODN decreased bcl-2 mRNA by 85%, compared with treatment with 500 nmol/L mismatch control ODN. Although bcl-2 expression levels in Shionogi cells were not changed by docetaxel treatment, docetaxel treatment induced bcl-2 phosphorylation. Consequently, the formation of bcl-2/Bax heterodimer formation was inhibited in a dose-dependent manner. Treatment of Shionogi tumors in vitro with either 500 nmol/L antisense bcl-2 ODN or 10 nmol/L docetaxel alone did not induce apoptosis or reduce growth rates. However, combined treatment reduced the concentration that reduces cell viability by 50% (IC50) of docetaxel from 100 nmol/L to 10 nmol/L and induced characteristic apoptotic DNA laddering and cleavage of the poly(ADP-ribose)polymerase (PARP) protein. Adjuvant in vivo administration of antisense bcl-2 ODN and polymeric micellar paclitaxel after castration resulted in a significant delay in time to Al recurrence when compared with administration of either agent alone. Furthermore, combined treatment of mice bearing Al recurrent Shionogi tumors with antisense bcl-2 ODN and micellar paclitaxel synergistically induced tumor regression and growth inhibition when compared with treatment with either agent alone. These findings suggest that down-regulation of bcl-2 by antisense ODN chemosensitizes Al Shionogi tumors to taxanes, over and above the effects of taxane-induced phosphorylation of bcl-2. Antisense bcl-2 ODN combined with taxanes may be a novel approach to the treatment of both established and emerging Al disease.
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PMID:Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides. 1060 83


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