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)

Oligosaccharides expressed by the 3327-H and 3327-MAT LyLu sublines of the Dunning rat prostate cancer model have been compared in formalin-fixed and routinely paraffin-embedded tumour tissues. Binding by lectins of defined specificity has been employed to identify expression of seven oligosaccharide structures by primary and metastatic prostatic carcinoma cells. Neuraminidase digestion was employed to reveal determinants masked by sialic acid. The presence of core Man alpha 1----3(Man alpha 1----6)Man beta 1----4GlcNAc beta 1----4 determinants recognised by Con-A (Canavalia ensiformis) confirmed expression of complex-type glycoconjugates by plasma membrane and cytoplasmic components of the 3327-H tumour but only by cytoplasmic determinants within 3327 MAT LyLu variant tumour-cells. The only other oligosaccharide freely expressed by either tumour-subline was (GlcNAc beta 1----4GlcNAc beta 1----4-)n, recognised by WGA (Triticum vulgaris). Prior to neuraminidase digestion, PNA (Arachis hypogaea) (which identifies Type I oligosaccharides: Gal beta 1----3GalNAc-) bound to pseudoluminal membranes of the 3327-H tumour. However, ECG (Erythrina cristagalli) (which identifies type II oligosaccharides: Gal beta 1----4GlcNAc-) did not bind to this tumour. Unmasked Type I (Gal beta 1----3GalNAc-) and Type II (Gal beta 1----4GlcNAc-) oligosaccharides were not identified in the MAT-LyLu variant. After neuraminidase digestion, PNA-binding was identified along pseudoluminal plasma membranes within 3327-H tumours but only within the cytoplasm of 3327-MAT LyLu primary and metastatic tumour cells. Following neuraminidase digestion, ECG-binding was observed along pseudoluminal plasma membranes of 3327-H tumours and heterogeneously within the cytoplasm of primary, but not metastatic 3327-MAT LyLu tumours. Terminal alpha/beta GalNAc- residues recognised by SBA (Glycine max) were not freely expressed by either subline. These structures were readily detected along luminal membranes of 3327-H cells and weakly detected within the cytoplasm of primary but not metastatic MAT 3327-LyLu tumour cells following neuraminidase digestion. Fucosylated Type II structures Fuc alpha 1----2Gal(GalNAc)-), recognised by UEA-1 (Ulex europaeus-1) and GalNAc alpha 1----3GalNAc- structures recognised by DBF (Dolichos biflorus) were not identified as a component of either tumour subline. The different patterns of oligosaccharide expression, identified by lectin-binding, clearly differentiated between the two tumour sublines and distinguished them from normal prostatic epithelium. The Dunning 3327 rat prostatic cancer sublines offer a useful model with which to examine the relationship between cell-surface oligosaccharide structures and phenotypic variants within a defined tumour-cell population.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differences in expression of oligosaccharide determinants by phenotypically distinct sublines of the Dunning 3327 rat prostate cancer. 238 49

Prostate cancer is the most common internal malignancy in men in the United States. Most cancers are diagnosed when they are locally advanced or metastatic and there is no effective treatment. In this study we evaluated the effectiveness of cytotoxic gene therapy in human PC-3 and DU145 prostate cancer cell lines and in a rodent cell line, RM-1, derived from the mouse prostate reconstitution model system. The cell lines were efficiently transduced in vitro by a replicative-defective recombinant adenovirus (ADV) carrying the herpes simplex virus thymidine kinase gene (HSV-tk). A virus titer-dependent sensitivity to ganciclovir (GCV) was observed. To determine a target therapeutic viral dose in vivo, subcutaneous tumors were generated by injection of RM-1 cells in syngeneic male hosts and injected with escalating doses of HSV-tk virus (5 x 10(7) to 1 x 10(9) pfu). The mice received GCV twice daily for 6 days and were sacrificed when tumor volumes exceeded 2.5 cm3 or when they appeared to be in distress. Because the two highest doses were equally as effective, further controlled studies were performed with the lower dose of 5 x 10(8) pfu with ADV/RSV-tk or a control virus containing the beta-galactosidase gene (ADV/RSV-beta-Gal) and treated with GCV or saline (PBS). The mean tumor volume in the treated animals was 16% that of control animals at 13 days. Histologically, treated tumors demonstrated necrosis and had a significantly higher apoptotic index. Survival data indicated that the treatment animals lived 7 days (21 in total) longer than the control animals, with 1 treatment animal being totally free of tumor. These results demonstrate that HSV-tk + GCV cytotoxic gene therapy can inhibit the growth of mouse and human prostate cancer cells in vitro and interrupt tumor growth of an aggressive mouse prostate cancer cell line in vivo.
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PMID:Prostate cancer gene therapy: herpes simplex virus thymidine kinase gene transduction followed by ganciclovir in mouse and human prostate cancer models. 880 Jul 46

Prostate carcinoma LNCaP cells were unique among several human cancer cell lines which include two other prostate cancer cell lines, PC-3 and DU-145, in expressing alpha1,2-L-fucosyltransferase (FT) as an exclusive FT activity. Affinity gel-GDP and Sephacryl S100 HR columns were used for a partial purification of this enzyme from 3.9 x 10(9) LNCaP cells (approximately 200-fold; 40% yield). The K(m) value (2.7 mM) for the LacNAc type 2 acceptor was quite similar to the one reported for the cloned blood group H gene-specified alpha1,2-FT [Chandrasekaran et al. (1996) Biochemistry 35, 8914-8924]. N-Ethylmaleimide was a potent inhibitor (K(i ) 12.5 microM). The enzyme showed four-fold acceptor preference for the LacNAc type 2 unit in comparison to the T-hapten in mucin core 2 structure. Its main features were similar to those of the cloned enzyme: (1) C-6 sulfation of terminal Gal in the LacNAc unit increased the acceptor efficiency, whereas C-6 sialylation abolished acceptor ability; (2) C-6 sulfation of GlcNAc in LacNAc type 2 decreased by 80% the acceptor ability, whereas LacNAc type 1 was unaffected; (3) Lewis x did not serve as an acceptor; (4) the C-4 hydroxyl rather than the C-6 hydroxyl group of the GlcNAc moiety in LacNAc type1 was essential for activity; and (5) the acrylamide copolymer of Galbeta1,3GlcNAcbeta-O-Al was the best acceptor among the acrylamide copolymers. Additionally, highly significant biological features of alpha1,2FT were identified in the present study. The synthesis of Globo H and Lewis b determinants became evident from the fact that Galbeta1,3GalNAcbeta1,3Galalpha-O-Me and Galbeta1,3(Fucalpha1,4)Glc-NAcbeta1,3Galbeta-O-Me served as high-affinity acceptors for this enzyme. Further, D-Fucbeta1,3Gal-NAcbeta1,3Galalpha-O-Me was a very efficient acceptor, indicating that the C-6 hydroxyl group of the terminal Gal moiety in Globo H is not essential for the enzyme activity. Thus, the present study was able to demonstrate three different catalytic roles of LNCaP alpha1,2-FT, namely, the expressions of blood group H, Lewis b from Lewis a, and Globo H.
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PMID:Biosynthesis of the carbohydrate antigenic determinants, Globo H, blood group H, and Lewis b: a role for prostate cancer cell alpha1,2-L-fucosyltransferase. 1197 59

The purpose of this study was to develop a model that investigates the biology of prostate cancer (PCA) that is metastatic to the bone, while closely approximates the clinical presentation of this disease. Human prostate cancer PC-3 cells were transfected with the neolacZ retrovirus. Then, eight-week-old SCID mice were injected subcutaneously with a single dose of PC-3 neolacZ cells. When the mice developed tumors at the injection site, they were sacrificed to harvest tumor fragments. One tumor fragment from a single PC-3 neolacZ injected animal was implanted into the prostates of five SCID mice. The SCID mice had all been previously grafted with adult human bone. Mice were sacrificed and tumor growth and metastasis to murine tissues as well as to the human bone graft were sought. The histologic samples were stained with X-Gal. In three mice tumors metastasized to the skeletal system. One animal showed limited X-Gal staining of the cells surrounding the human bone implant. In two mice tumors metastasized to liver and kidney and one metastasized to the lung. In this study we established a spontaneous bone metastasis model of human PCA cells with the combination of lacZ expression and orthotopic implantation of the PC-3 implanted tumor fragments. This model offers potential advantages in monitoring the metastatic pattern and behavior of prostate cancer and may be used to selectively study its interaction with human bone.
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PMID:A metastatic human prostate cancer model using intraprostatic implantation of tumor produced by PC-3 neolacZ transfected cells. 1461 28

Sialic acids are key determinants in many carbohydrates involved in biological recognition. We studied the acceptor specificities of three cloned sialyltransferases (STs) [alpha2,3(N)ST, alpha2,3(O)ST, and alpha2,6(N)ST] and another alpha2,3(O)ST present in prostate cancer cell LNCaP toward mucin core 2 tetrasaccharide [Galbeta1,4GlcNAcbeta1,6(Galbeta1,3)GalNAcalpha-O-Bn] and Globo [Galbeta1,3GalNAcbeta1,3Galalpha-O-Me] structures containing sialyl, fucosyl, sulfo, methyl, or fluoro substituents by identifying the products by electrospray ionization tandem mass spectral analysis and other biochemical methods. The Globo precursor was an efficient acceptor for both alpha2,3(N)ST and alpha2,3(O)ST, whereas only alpha2,3(O)ST used its deoxy analogue (d-Fucbeta1,3GalNAcbeta1,3-Gal-alpha-O-Me); 2-O-MeGalbeta1,3GlcNAc and 4-OMeGalbeta1,4GlcNAc were specific acceptors for alpha2,3(N)ST. Other major findings of this study include: (i) alpha2,3 sialylation of beta1,3Gal in mucin core 2 can proceed even after alpha1,3 fucosylation of beta1,6-linked LacNAc. (ii) Sialylation of beta1,3Gal must precede the sialylation of beta1,4Gal for favorable biosynthesis of mucin core 2 compounds. (iii) alpha2,3 sialylation of the 6-O-sulfoLacNAc moiety in mucin core 2 (e.g., GlyCAM-1) is facilitated when beta1,3Gal has already been alpha2,3 sialylated. (iv) alpha2,6(N)ST was absolutely specific for the beta1,4Gal in mucin core 2. Either alpha1,3 fucosylation or 6-O-sulfation of the GlcNAc moiety reduced the activity. Sialylation of beta1,3Gal in addition to 6-O-sulfation of GlcNAc moiety abolished the activity. (v) Prior alpha2,3 sialylation or 3-O-sulfation of beta1,3Gal would not affect alpha2,6 sialylation of Galbeta1,4GlcNAc of mucin core 2. (vi) A 3- or 4-fluoro substituent in beta1,4Gal resulted in poor acceptors for the cloned alpha2,6(N)ST and alpha2,3(N)ST, whereas 4-fluoro- or 4-OMe-Galbeta1,3GalNAcalpha was a good acceptor for cloned alpha2,3(O)ST. (vii) 4-O-Methylation of beta1,4Gal abolished the acceptor ability toward alpha2,6(N)ST but increased the acceptor efficiency considerably toward alpha2,3(N)ST. (viii) Just like LNCaPalpha1,2-FT and Gal-3-O-sulfotransferase T2, the cloned alpha2,3(N)ST which modifies terminal Gal in Galbeta1,4GlcNAc also efficiently utilizes the terminal beta1,3Gal in the Globo backbone. Utilization of C-3 blocked compounds such as 3-O-sulfo-Galbeta1,3GalNAcbeta1,3Galalpha-OMe as acceptors by cloned alpha2,3(O)ST and analyses of the resulting products by lectin chromatography and mass spectrometry indicate that alpha2,3(O)ST is capable of attaching NeuAc to another position in C-3-substituted beta1,3Gal.
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PMID:Analysis of the specificity of sialyltransferases toward mucin core 2, globo, and related structures. identification of the sialylation sequence and the effects of sulfate, fucose, methyl, and fluoro substituents of the carbohydrate chain in the biosynthesis of selectin and siglec ligands, and novel sialylation by cloned alpha2,3(O)sialyltransferase. 1630 Apr 12

Prostate cancer is one of the malignant tumors which exhibit resistance to anticancer drugs, at least in part due to enhanced antiapoptotic mechanisms. Therefore, the understanding of such mechanisms should improve the design of chemotherapy against prostate cancer. Galectin-3 (Gal-3), a multifunctional oncogenic protein involved in the regulation of tumor proliferation, angiogenesis, and apoptosis has shown antiapoptotic effects in certain cell types. Here, we show that the expression of exogenous Gal-3 in human prostate cancer LNCaP cells, which do not express Gal-3 constitutively, inhibits anticancer drug-induced apoptosis by stabilizing the mitochondria. Thus, Gal-3-negative cells showed 66.31% apoptosis after treatment with 50 micromol/L cis-diammine-dichloroplatinum for 48 hours, whereas two clones of Gal-3-expressing cells show only 2.92% and 1.42% apoptotic cells. Similarly, Gal-3-negative cells showed 43.8% apoptosis after treatment with 300 micromol/L etoposide for 48 hours, whereas only 15.38% and 14.51% of Gal-3-expressing LNCaP cells were apoptotic. The expression of Gal-3 stimulated the phosphorylation of Ser(112) of Bcl-2-associated death (Bad) protein and down-regulated Bad expression after treatment with cis-diammine-dichloroplatinum. Gal-3 also inhibited mitochondrial depolarization and damage after translocation from the nuclei to the cytoplasm, resulting in inhibition of cytochrome c release and caspase-3 activation. These findings indicate that Gal-3 inhibits anticancer drug-induced apoptosis through regulation of Bad protein and suppression of the mitochondrial apoptosis pathway. Therefore, targeting Gal-3 could improve the efficacy of anticancer drug chemotherapy in prostate cancer.
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PMID:Galectin-3 regulates mitochondrial stability and antiapoptotic function in response to anticancer drug in prostate cancer. 1654 Jun 61

Prostate-specific membrane antigen (PSMA) is a membrane-bound antigen expressed on the surface of prostate cancer cells, and this paper describes the use of an antibody against PSMA for targeting gene therapy. We coupled anti-PSMA monoclonal antibody with poly-L-lysine and then incubated it with plasmids. These complexes were then transfected with cationic liposomes into cells. The transfection efficiency of anti-PSMA- liposome complex was higher than that of normal IgG-liposome complex in PSMA-positive LNCaP cells. Furthermore, anti-PSMA-liposome complex containing a suicide gene, thymidine kinase, demonstrated a selective growth-inhibitory effect on LNCaP cells in vitro, but did not exert a significant effect on PSMA-negative cells. In an in vivo xenograft model of LNCaP cells in nu/nu mice, we administered the complexes via the tail vein. Judging on the basis of both 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-Gal) staining and luciferase assay findings, a significant enrichment of plasmid DNA was observed in LNCaP xenografts with anti-PSMA-liposome complex in comparison with normal IgG-liposome complex. However, the distribution of plasmid DNA did not change substantially in any other organs including the liver, kidney, lung, and spleen. Moreover, in suicide gene therapy, anti-PSMA-liposome complex exerted a significant inhibitory effect on the growth of LNCaP xenograft, in contrast to normal IgG-liposome complex.
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PMID:Targeting gene therapy for prostate cancer cells by liposomes complexed with anti-prostate-specific membrane antigen monoclonal antibody. 1703 55

Prostate cancer will develop chemoresistance following a period of chemotherapy. This is due, in part, to the acquisition of antiapoptotic properties by the cancer cells and, therefore, development of novel strategies for treatment is of critical need. Here, we attempt to clarify the role of the antiapoptotic molecule galectin-3 in prostate cancer cells using siRNA and antagonist approaches. The data showed that Gal-3 inhibition by siRNA or its antagonist GCS-100/modified citrus pectin (MCP) increased cisplatin-induced apoptosis of PC3 cells. Recent studies have indicated that cisplatin-induced apoptosis may be mediated by calpain, a calcium-dependent protease, as its activation leads to cleavage of androgen receptor into an androgen-independent isoform in prostate cancer cells. Thus, we examined whether calpain activation is associated with the Gal-3 function of regulating apoptosis. Here, we report that Gal-3 inhibition by siRNA or GCS-100/MCP enhances calpain activation, whereas Gal-3 overexpression inhibits it. Inhibition of calpain using its inhibitor and/or siRNA attenuated the proapoptotic effect of Gal-3 inhibition, suggesting that calpain activation may be a novel mechanism for the proapoptotic effect of Gal-3 inhibition. Thus, a paradigm shift for treating prostate cancer is suggested whereby a combination of a non-toxic anti-Gal-3 drug together with a toxic chemotherapeutic agent could serve as a novel therapeutic modality for chemoresistant prostate cancers.
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PMID:Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment. 2136 66

The intermediate nucleus (InM) in the preoptic area of the human brain, also known as the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the interstitial nucleus of the anterior hypothalamus-1 (INAH-1) is explored here. We investigated its population of galanin-immunoreactive (Gal-Ir) neurons in relation to sex, age, and gender identity in the postmortem brain of 77 subjects. First we compared the InM volume and number of Gal-Ir neurons of 22 males and 22 females in the course of aging. In a second experiment, we compared for the first time the InM volume and the total and Gal-Ir neuron number in 43 subjects with different gender identities: 14 control males (M), 11 control females (F), 10 male-to-female (MtF) transsexual people, and 5 men who were castrated because of prostate cancer (CAS). In the first experiment we found a sex difference in the younger age group (<45 years of age), i.e., a larger volume and Gal-Ir neuron number in males and an age difference, with a decrease in volume and Gal-Ir neuron number in males > 45 years. In the second experiment the MtF transsexual group presented an intermediate value for the total InM neuron number and volume that did not seem different in males and females. Because the CAS group did not have total neuron numbers that were different from the intact males, the change in adult circulating testosterone levels does not seem to explain the intermediate values in the MtF group. Organizational and activational hormone effects on the InM are discussed.
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PMID:Galanin neurons in the intermediate nucleus (InM) of the human hypothalamus in relation to sex, age, and gender identity. 2161 23

Galectin-3 (Gal-3), over-expressed on a variety of human tumor cells, is a potential binding site for targeted metastatic prostate cancer therapy. The aim of this study was to develop a G3-C12-mediated drug delivery system based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers targeting to Gal-3-expressed human PC-3 prostate carcinoma cells. 5-Fluorouracil (5-Fu), an anti-tumor agent, was selected as a model drug. G3-C12, a binding peptide, which specifically binds to the carbohydrate-recognition domain (CRD) of Gal-3, was attached to HPMA copolymers as a targeting moiety. Compared with non-targeted conjugates (P-Fu), Gal-3-targeted HPMA copolymer-(G3-C12)-5-Fu conjugates (P-(G3-C12)-Fu) displayed a superior intracellular internalization followed by enhanced cytotoxicity and apoptosis-induction. Subsequently, the in vitro migration study on PC-3 cells indicated that P-(G3-C12)-Fu was able to efficiently inhibit the cell migration ability after wounding. On PC-3 tumor-bearing mice model, G3-C12-modified copolymers showed a higher tumor accumulation coupled with a faster clearance from blood circulation than non-modified ones. Finally, Gal-3-targeted conjugates significantly improved the anti-tumor activity of 5-Fu in nude mice bearing PC-3 tumor xenografts. Consequently, G3-C12 would be a promising targeting moiety for cell-specific prostate cancer therapy in future.
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PMID:Treatment of prostate carcinoma with (galectin-3)-targeted HPMA copolymer-(G3-C12)-5-Fluorouracil conjugates. 2218 43


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