Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study evaluated the in vitro effect of L-canavanine on cell cycle progression in the two human pancreatic cancer cells lines PANC-1 and MIA PaCa-2. After 72 h of exposure to L-canavanine, the percentage of cells in the radiosensitive G2/M phase of the cell cycle increased 6-fold in PANC-1 cells and 4-fold in MIA PaCa-2 cells, when compared to untreated cells. The capacity of L-canavanine to redistribute cells into the G2/M phase of the cell cycle was both concentration- and time-dependent. Since many drugs that cause cells to accumulate in the G2/M phase of the cell cycle are effective radiosensitization agents, the potential of L-canavanine to synergistically enhance the effects of ionizing radiation also was evaluated. The interaction between these treatment modalities was quantified using the median-effect equation and combination index analysis. L-Canavanine was found to be synergistic with radiation when either PANC-1 or MIA PaCa-2 cells were exposed to L-canavanine for 72 h prior to irradiation. These results suggest that L-canavanine in combination with radiation may have clinical potential in the treatment of pancreatic cancer.
Mol Cell Biochem 2003 Feb
PMID:L-Canavanine as a radiosensitization agent for human pancreatic cancer cells. 1270 7

Neurotensin (NT) receptors are overexpressed in exocrine pancreatic cancer and Ewing's sarcoma. The potential utility of native NT in cancer diagnosis and therapy is, however, limited by its rapid degradation in vivo. Therefore, NT analogues were synthesised with modified lysine and arginine derivatives to enhance stability and coupled either to DTPA, to enable high specific activity labelling with indium-111 for imaging, or to DOTA, to enable high specific activity labelling with beta-emitting radionuclides, such as lutetium-177 and yttrium-90. Based on serum stability (4 h incubation at 37 degrees C in human serum) and receptor binding affinity, the five most promising analogues were selected and further evaluated in in vitro internalisation studies in human colorectal adenocarcinoma HT29 cells, which overexpress NT receptors. All five NT analogues bound with high affinity to NT receptors on human exocrine pancreatic tumour sections. The analogues could be labelled with (111)In to a high specific activity. The (111)In-labelled compounds were found to be very stable in serum. Incubation of HT29 cells with the (111)In-labelled analogues at 37 degrees C showed rapid receptor-mediated uptake and internalisation. The most promising analogue, peptide 2530 [DTPA-(Pip)Gly-Pro-(PipAm)Gly-Arg-Pro-Tyr-tBuGly-Leu-OH] was further tested in vivo in a biodistribution study using HT29 tumour-bearing nude mice. The results of this study showed low percentages of injected dose per gram tissue of this (111)In-labelled 2530 analogue in receptor-negative organs like blood, spleen, pancreas, liver, muscle and femur. Good uptake was found in the receptor-positive HT29 tumour and high uptake was present in the kidneys. Co-injection of excess unlabelled NT significantly reduced tumour uptake, showing that tumour uptake is a receptor-mediated process. With their enhanced stability, maintained high receptor affinity and rapid receptor-mediated internalisation, the (111)In-labelled DTPA- and DOTA-conjugated NT analogues are excellent candidates for imaging and therapy of exocrine pancreatic cancer, peptide 2530 being the most promising analogue.
Eur J Nucl Med Mol Imaging 2003 Aug
PMID:Stabilised 111In-labelled DTPA- and DOTA-conjugated neurotensin analogues for imaging and therapy of exocrine pancreatic cancer. 1276 32

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. To improve diagnosis and treatment, key mechanisms of deregulated molecular functions have to be identified. Using microarray analysis, the expression patterns of 5600 human genes were assessed in PDAC by comparison with the normal pancreas and chronic pancreatitis (CP). The expression of 467 of 5600 genes was increased in PDAC in comparison to the normal pancreas, and the expression of 120 of these genes was not increased in CP. In addition, 341 of 5600 genes were expressed at decreased levels in PDAC tissues, of which 96 were decreased in comparison to both normal and CP tissues. Thus, a total of 808 of 5600 human genes were differentially expressed in pancreatic cancer. The identification of a large panel of altered genes in PDAC will stimulate additional studies that will lead to improved understanding of the molecular mechanisms underlying pancreatic malignant growth.
Cell Mol Life Sci 2003 Jun
PMID:Microarray-based identification of differentially expressed growth- and metastasis-associated genes in pancreatic cancer. 1286 84

Human BCL9 gene is over-expressed in some cases of acute lymphoblastic leukemia (ALL) with t(1;14)(q21;q32). Drosophila segment polarity gene legless (lgs), encoding wingless-armadillo (WNT - beta-catenin) signaling molecule, is the homolog of human BCL9. Here, we identified and characterized human BCL9-like (BCL9L) gene as well as mouse Bcl9-like (Bcl9l) gene by using bioinformatics. Uncharacterized DLNB11 cDNA (AB094091.1) was derived from human BCL9L gene. Nucleotide sequence of mouse Bcl9l cDNA was determined in silico by assembling mouse ESTs BF464707, BQ258167, 5'-truncated BC003321 cDNA, and mouse genome clone RP24-308H8 (AC125129.5). Human BCL9L and mouse Bcl9l genes were found to consist of eight exons. Exon-intron structure was well conserved between human BCL9L and mouse Bcl9l genes. Human BCL9L (1499 aa) showed 94.0% and 34.8% total-amino-acid identity with mouse Bcl9l (1494 aa) and human BCL9, respectively. Six domains (B9H1-B9H6) were conserved among mammalian BCL9 family proteins. B9H1 and B9H2 domains, and N-terminal part of B9H3 domain were identical to HD1, HD2, and HD3 domains conserved between human BCL9 and Drosophila lgs. B9H4, B9H5 and B9H6 were novel domains. B9H4 domain was characterized by multiple Ser-Pro repeats. Human BCL9L mRNA was expressed in fetal brain, adult lung, amygdala, eye, prostate, and also in several types of tumors including pancreatic cancer, prostate cancer, head and neck tumor and embryonal tumor. BCL9L gene was located between BLR1 and UPK2 genes within the commonly deleted region of neuroblastoma at human chromosome 11q23.3. This is the first report on human BCL9L and mouse Bcl9l.
Int J Mol Med 2003 Oct
PMID:Identification and characterization of human BCL9L gene and mouse Bcl9l gene in silico. 1296 48

In cells with an altered p53 gene, the expression of p21(WAF1/CIP1), a potent inhibitor of cyclin-dependent kinases, can be induced by histone deacetylase (HDAC) inhibitors via a p53-independent pathway, which may play a critical role in arrest of cell growth. Accordingly, HDAC inhibitors such as trichostatin A (TSA) have potential utility in pancreatic cancer, as most of these tumors possess mutations in p53, which in fact is the main cause of chemoresistance to 5-fluorouracil. We have analyzed the effect of TSA on the proliferation of nine pancreatic adenocarcinoma cell lines, all containing a mutated p53 gene. TSA strongly inhibited the cellular growth of all these cell lines at submicromolar concentrations. The cellular mechanisms underlying this effect consisted of cell cycle arrest at the G2 phase and apoptotic cell death. The expression of p21(WAF1/CIP1) normally induced at the transcriptional level by p53 was also strongly activated by TSA. These findings suggest that inhibitors of HDAC may represent a novel therapeutic strategy for treatment of pancreatic cancer.
Mol Carcinog 2003 Oct
PMID:Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells. 1450 45

Trypsinogen/trypsin is one of the major serine proteases and is produced by pancreatic acinar cells. Tumor-associated trypsinogen (TAT) has been reported to be produced by several cancer cell lines. The biological roles and activation mechanisms of both TAT and pancreatic acinar trypsinogen (PAT) have not been elucidated in the context of cancer extension, in particular at the stage of invasion and metastasis. In this study, we investigate the roles played by PAT and TAT in pancreatic cancer invasion. In addition, we determined their mechanisms of activation and identified a trypsinogen activity-stimulating factor (TASF) produced by pancreatic cancer cells. TAT expression and high TAT activity were associated with high invasive and liver metastatic potential in SW1990 and CAPAN-2 cells. Moreover, a trypsinogen activating effect and activity prolonging effect was observed in a mixture of these supernatants with trypsinogen. These cells revealed significantly enhanced invasiveness upon invasion assay and in the presence of PAT. TAT and PAT were activated by TASF, active u-PA, produced by pancreatic cancer cells. Activated TAT and PAT can degrade not only ECM proteins but they can also activate other latent proteases. This ECM-protease-network may form a vicious cycle, thereby promoting tumor cell invasion.
Int J Mol Med 2003 Dec
PMID:Identification of a trypsinogen activity stimulating factor produced by pancreatic cancer cells: its role in tumor invasion and metastasis. 1461 60

Pancreatic cancer is associated with the worst 5-year survival rate of any human cancer. This high mortality is due, in part, to difficulties in establishing early and accurate diagnosis. Because most tumours share the ability to accumulate amino acids more effectively than normal tissues and any other pathology, assessment of amino acid transport in tumour cells using radiolabelled amino acids has become one of the most promising tools for tumour imaging. This study investigated the potential of p-[(123)I]iodo-L-phenylalanine (IPA) for detection of pancreatic cancer by single-photon emission tomography. IPA affinity for pancreatic tumour was investigated in human pancreatic adenocarcinoma PaCa44 and PanC1 cells, followed by analysis of the underlying mechanisms of tracer accumulation in neoplastic cells. Thereafter, IPA was evaluated for targeting of pancreatic tumours using SCID mice engrafted with primary human pancreatic adenocarcinoma cells, as well as in acute inflammation models in immunocompetent mice and rats. IPA accumulated intensively in human pancreatic tumour cells. Radioactivity accumulation in tumour cells following a 30-min incubation at 37 degrees C/pH 7.4 varied from 41% to 58% of the total loaded activity per 10(6) cells. The cellular uptake was temperature and pH dependent and predominantly mediated by specific carriers for neutral amino acids, namely the sodium-independent and L-leucine-preferring (L-system) transporter and the alanine-, serine- and cysteine-preferring (ASC-system) transporter. Protein incorporation was less than 8%. Biodistribution studies showed rapid localization of the tracer to tumours, reaching 10%+/-2.5% to 15%+/-3% of the injected dose per gram (I.D./g) in heterotopic tumours compared with 17%+/-3.5% to 22%+/-4.3% I.D./g in the orthotopic tumours, at 60 and 240 min post injection of IPA, respectively. In contrast, IPA uptake in the gastrointestinal tract and areas of inflammation remained moderate and decreased with time. Excellent tumour detection was obtained by gamma camera imaging. The specific and high-level targeting of IPA to tumour and the negligible uptake in the gastrointestinal tract and areas of inflammation indicate that p-[(123)I]iodo-L-phenylalanine is a promising tracer for differential diagnosis of pancreatic cancer.
Eur J Nucl Med Mol Imaging 2004 Apr
PMID:p-[123I]iodo-L-phenylalanine for detection of pancreatic cancer: basic investigations of the uptake characteristics in primary human pancreatic tumour cells and evaluation in in vivo models of human pancreatic adenocarcinoma. 1472 85

The stromal cell-derived factor-1 (SDF-1)/CXCR4 system is implicated in various instances of cell migration in mammals, including the migration of lymphocytes and the formation of metastases. We have recently synthesized a potent novel CXCR4 antagonist, TN14003. The purpose of this study was to investigate the role of SDF-1/CXCR4 axis in the pancreatic cancer metastasis via cell migration and invasion, and the inhibitory effect of TN14003 on pancreatic cancer cell metastasis. The expression of CXCR4 was detected in six pancreatic cancer cell lines by Western blotting and immunocytochemistry. In migration and invasion assays, SDF-1 stimulated both migration and invasion of cancer cells in a dose-dependent manner. The maximal effect of SDF-1 was observed at 100 ng/ml. SDF-1-induced migration and invasion of cancer cells were completely blocked by 100 nM TN14003. The stimulatory effect of SDF-1 on cancer migration and the inhibitory effect of TN14003 were mediated via the alteration in phosphorylation of mitogen-activated protein kinases. Treatment of cancer cells with 100 ng/ml SDF-1 resulted in a significant increase of actin polymerization, which was reduced by 100 nM TN14003. SDF-1 enhanced cancer cell adhesion to laminin, which was not reversed by TN14003. Taken together, SDF-1/CXCR4 axis is involved in pancreatic cancer metastasis through migration and invasion. The small molecule antagonists against CXCR4 such as TN14003 might be an effective anti-metastatic agent for pancreatic cancer.
Mol Cancer Ther 2004 Jan
PMID:CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer. 1474 73

Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative, which is a selective and potent inhibitor of the proteasome. We examined the antitumor activity of combination therapy with bortezomib + docetaxel in two human pancreatic cancer cell lines (MiaPaCa-2 and L3.6pl) selected for their divergent responses to bortezomib alone. Bortezomib blocked docetaxel-induced apoptosis in the MiaPaCa-2 cells and failed to enhance docetaxel-induced apoptosis in L3.6pl cells in vitro but did interact positively with docetaxel to inhibit clonogenic survival. These effects were associated with decreased accumulation of cells in M phase, stabilization of the cyclin-dependent kinase inhibitors, p21 and p27, and inhibition of cdk2 and cdc2 activities. In orthotopic xenografts, combination therapy produced significant reductions in tumor weight and volume in both models associated with accumulation of p21, inhibition of proliferation, and increased apoptosis. Combination therapy also reduced tumor microvessel densities, effects that were associated with reductions in tumor cell production of vascular endothelial growth factor and increased levels of apoptosis in tumor-associated endothelial cells. Together, our results suggest that bortezomib enhances the antitumoral activity of taxanes by enforcing cell growth arrest and inhibiting angiogenesis.
Mol Cancer Ther 2004 Jan
PMID:The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts. 1474 76

Formin homology proteins with FH1 and FH2 domains are signaling effectors for assembly and polarization of actin filaments. FH1 is the binding domain for Profilin, SRC, EMS1/Cortactin, FNBP1, FNBP2, FNBP3, FNBP4 and WBP4/Fbp21, while FH2 is the actin-filament modification domain. Here, we identified and characterized a novel member of Formin-homology gene family, Diaphanous homology 3 (DIAPH3), by using bioinformatics. DIAPH3 isoform 1, corresponding to 3'-truncated FLJ34705 cDNA and 5'-divergent IMAGE5265490 cDNA, encodes full-length DIAPH3 protein (1112 aa), while DIAPH3 isoform 2, identical to NM_030932.2 cDNA, encodes N-terminally truncated DIAPH3 protein (849 aa). DIAPH3 isoform 1, consisting of exons 1-27, was expressed in lymph node, erythroid progenitor cells as well as in pancreatic cancer. DIAPH3 isoform 2, consisting of exons 1b and 8-27, was expressed in testis. DIAPH3 gene at human chromosome 13q21.2 was found to encode two isoforms due to alternative splicing of the alternative promoter type. Full-length human DIAPH3 protein, consisting of FDD, FH1 and FH2 domains, showed 51.3% total-amino-acid identity with DIAPH1, and 57.3% total-amino-acid identity with DIAPH2. FMNL1/FMNL, FMNL2/FHOD2, FMNL3/WBP3, DAAM1, DAAM2, DIAPH1, DIAPH2 and DIAPH3 were classified as the FDD-type Formin homology proteins, while GRID2IP/Delphilin, FHOD1, Fmn1 and Fmn2 were classified as the non-FDD-type Formin homology proteins. This is the first report on identification and characterization of human DIAPH3 gene.
Int J Mol Med 2004 Mar
PMID:Identification and characterization of human DIAPH3 gene in silico. 1476 82


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