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: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of neurotensin on pancreatic carcinogenesis induced by azaserine was investigated in Wistar rats. Rats were given weekly injections of 10 mg/kg body weight of azaserine for 25 weeks and 200 micrograms/kg body weight of neurotensin in depot form every other day for 62 weeks. Carcinogen-induced pancreatic lesions were examined by histochemical techniques, and were classified as ATPase-positive or ATPase-negative. In week 62, quantitative histological analysis showed that prolonged administration of neurotensin significantly reduced the volume (as percent of parenchyma) of ATPase-positive pancreatic lesions, which are closely correlated with the ultimate development of pancreatic cancer. Histologically, pancreatic adenocarcinomas occurred at a significantly lower rate in rats treated with neurotensin than in untreated rats. Administration of neurotensin also significantly decreased the labelling indices of carcinogen-induced pancreatic lesions, but not of the surrounding acinar cells. These findings indicate that neurotensin inhibits pancreatic carcinogenesis, and that this may be related to the reduction of ATPase-positive lesions and to the inhibition of cell proliferation in neoplastic lesions of the pancreas.
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PMID:Inhibition by neurotensin of azaserine-induced carcinogenesis in rat pancreas. 199 48

Transgenic mice bearing the rat elastase I promoter - SV40 T-antigen (ELSV) fusion gene develop pancreatic acinar cell carcinomas by 3-6 months of age. In other animal models of pancreatic cancer, cholecystokinin (CCK) has been shown to be a tumor promoter. Therefore, we characterized CCK binding properties and CCK-A receptor mRNA expression in pancreatic carcinomas and dysplastic pancreata from the Tg(Ela-1, SV40E+Ela-1, neo)Bri19 strain of ELSV transgenic mice. To accomplish this, we utilized 125I-Bolton-Hunter-labeled-cholecystokinin octapeptide (125I-BH-CCK-8) binding studies, reverse transcription-polymerase chain reaction (RT-PCR), and Southern blot analysis to examine pancreatic carcinomas from 26-week-old male ELSV transgenic mice, dysplastic pancreata from 8-week-old male ELSV transgenic mice, and normal pancreas from 30-week-old nontransgenic male mice (SJL/J) and 8-week-old nontransgenic male mice (B6SJLF1/J). Optimal saturable CCK-8 binding was detected at pH 6.5, 22 degrees C. Competitive inhibition 125I-BH-CCK-8 binding assays performed on all four mouse pancreatic tissues showed that CCK-8 bound to two classes of CCK binding sites: a high affinity, lower capacity CCK binding site and a low affinity, higher capacity CCK binding site. RT-PCR and Southern blot analysis confirmed the 125I-BH-CCK-8 binding studies by demonstrating CCK-A receptor mRNA expression in the ELSV transgenic pancreatic carcinomas and dysplastic pancreas, as well as in normal nontransgenic mouse pancreas. In conclusion, pancreatic carcinomas and dysplastic pancreas from ELSV transgenic mice and normal nontransgenic mouse pancreas all bind 125I-BH-CCK-8 and express mRNA for the CCK-A receptor. In contrast to chemically-induced pancreatic tumors in the rat, ELSV transgenic mouse pancreatic tumors do not appear to significantly overexpress CCK-A receptors.
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PMID:Cholecystokinin receptor characterization and cholecystokinin-A receptor messenger RNA expression in transgenic mouse pancreatic carcinomas and dysplastic pancreas. 770 27

To understand the mechanism of action of the antitumor arotinoid mofarotene (Ro 40-8757), differential screening of cDNA libraries with cDNA probes prepared from treated or untreated breast-cancer cells was performed. Several genes were identified that appeared to be regulated by mofarotene, including a mitochondrial gene encoding a subunit of NADH dehydrogenase (NDI). This gene was down-regulated in the breast-cancer cell line MDA-MB-231 after treatment with the arotinoid for 3 to 6 hr. Down-regulation of NDI was detected in 2 other breast-carcinoma cell lines (ZR-75-I and MCF-7) and a pancreatic cancer cell line (BxPC3), but not in the normal fibroblast cell line Wi-38 or several other tumor cell lines. This effect was blocked by addition of cycloheximide to the medium. The retinoids, all-trans and 9-cis retinoic acids, did not affect the expression of NDI in MDA-MB-231 cells, demonstrating that mofarotene was not acting through the nuclear retinoic-acid receptors. In the estrogen-receptor-expressing breast-cancer line ZR-75-I, tamoxifen had no effect on NDI expression. The cytotoxic drugs doxorubicin, 5-FU and vincristine also had no effect on regulation of this gene. Two mitochondrial proteins encoded in the nucleus, ATPase beta subunit and mitochondrial transcription factor I, were not down-regulated by mofarotene. Addition of mofarotene to cells incubated in glucose-free medium led to their death. These results indicate that down-regulation of mitochondrial gene transcription is specific to mofarotene and may explain, in part, the anti-proliferative effects of this compound.
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PMID:Down-regulation of mitochondrial gene expression by the anti-tumor arotinoid mofarotene (Ro 40-8757). 792 84

The effects of prolonged administration of the diuretic amiloride on pancreatic carcinogenesis induced by azaserine and on the labeling index of carcinogen-induced pancreatic lesions were investigated in Wistar rats. Rats were given 25 weekly injections of 10 mg/kg body weight azaserine and also 5 mg/kg body weight amiloride every other day until the end of the experiment at week 62. Carcinogen-induced pancreatic lesions were examined by histochemical techniques and were classified as ATPase-positive or ATPase-negative. In week 62, quantitative histologic analysis showed that prolonged administration of amiloride significantly reduced the number and size (as percent of parenchyma) of ATPase-positive pancreatic lesions, which are closely correlated with the subsequent development of pancreatic cancer. Amiloride also significantly decreased the labeling index of carcinogen-induced pancreatic lesions, but not of the surrounding acinar cells. In contrast, amiloride has no significant influence on the number and size of ATPase-negative pancreatic lesions. These findings indicate that amiloride inhibits pancreatic carcinogenesis, and that this effect may be related to the reduction of ATPase-positive lesions and to amiloride's inhibition of cell proliferation in neoplastic lesions of the pancreas.
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PMID:Inhibition by amiloride of experimental carcinogenesis induced by azaserine in rat pancreas. 882 43

The effects of galanin on pancreatic carcinogenesis induced by azaserine and on the norepinephrine concentration in the pancreas were investigated in male Wistar rats. Rats were given weekly injections of 10 mg/kg body weight of azaserine for 25 weeks and 8 microg/kg body weight of galanin in depot form every other day for 62 weeks. Azaserine-induced pancreatic lesions were examined with hematoxylin and eosin and histochemical techniques. In week 62, quantitative histological examination showed that prolonged administration of galanin significantly reduced the number and size (as percent of parenchyma) of adenosine triphosphatase-positive pancreatic lesions, which are correlated closely with the ultimate development of pancreatic cancer. The number of pancreatic adenocarcinomas in rats treated with galanin was significantly less than in controls. Galanin also significantly decreased the bromodeoxyuridine-labeling index of azaserine-induced pancreatic lesions and the norepinephrine concentration in the pancreas. Our findings indicate that galanin inhibits pancreatic carcinogenesis and that such inhibition may be related to the suppression of sympathetic nervous system activity and subsequently to the inhibition of cell proliferation in neoplastic lesions of the pancreas.
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PMID:Inhibition by galanin of experimental carcinogenesis induced by azaserine in rat pancreas. 945

Bafilomycin A1, a specific inhibitor of vacuolar type H(+)-ATPase, can inhibit the growth of a variety of cultured cells in a dose-dependent manner, but its mechanism is unclear. The aim of this study was to examine whether bafilomycin A1 inhibits the growth of Capan-1 human pancreatic cancer cells through apoptosis. The effect of bafilomycin A1 on tumour growth in vitro and in vivo was examined using an MTT assay and an in vivo tumour model. The presence or absence of apoptosis was determined by morphology and DNA analysis of tumour cells. The concentration of bafilomycin A1 for 50 per cent inhibition of cell viability during 72 h by the MTT assay was 5 nm. In DNA analysis, a ladder of fragmented DNA was detected in Capan-1 cells treated with bafilomycin A1 at concentrations greater than 10 nm for 24 h. Nude mice bearing a xenografted Capan-1 cell line tumour received 4 weeks of bafilomycin A1 (1.0 mg/kg per day). This treatment significantly inhibited tumour growth compared with controls after 21 days (P < 0.05). Histopathological examination of tumour cells in the treated group demonstrated signs of apoptosis with chromatin condensation and cell shrinkage. These observations suggest that bafilomycin A1 inhibits the growth of Capan-1 human pancreatic cancer cells through apoptosis.
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PMID:Bafilomycin A1 induces apoptosis in the human pancreatic cancer cell line Capan-1. 977 88

Several inhibitors of angiogenesis have been identified in bovine and shark cartilage. One of them is troponin I, which is the molecule responsible for the inhibition of the actomyosin ATPase during muscle contraction. In this study we sought to investigate if the active site of troponin I (peptide Glu94-Leu123; pTnI) is also the one responsible for the antiangiogenic properties of this protein. The effects of pTnI on endothelial cell tube formation and endothelial cell division were investigated using human umbilical vein endothelial cells, Matrigel, light microscopy, carboxyfluorescein diacetate, succinimidyl esterlabeling, and flow cytometry. Its effects on induction of ICAM-1 and production of vascular endothelial growth factor by pancreatic cancer cells (CAPAN-1) were also investigated, as was its efficacy in a mouse model of pancreatic cancer metastases. Our results show that concentrations as low as 1 pg/ml of pTnI significantly inhibit endothelial cell tube formation, and that endothelial cell division was inhibited at 96 hours by 3 microg/ml pTnI (P=0.0001). No effects were seen using troponin peptide 124-181 as a control. pTnI-treated supernatant from the pancreatic cancer cell line CAPAN-1 downregulated ICAM-1 expression on human umbilical vein endothelial cells up to 10 ng/ml pTnI, and a significant reduction in vascular endothelial growth factor production was seen by treating CAPAN-1 cells with up to 1 microg/ml pTnI. After intrasplenic injection of CAPAN-1 cells, mice treated with pTnI had fewer liver metastases compared to control mice (liver/body weight 5.5 vs. 11.1; P=0.03). The active region of troponin I is the one responsible for its antiangiogenic effect. The mechanism of action of this peptide is probably multifactorial.
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PMID:Troponin I peptide (Glu94-Leu123), a cartilage-derived angiogenesis inhibitor: in vitro and in vivo effects on human endothelial cells and on pancreatic cancer. 1467 5

Among all human carcinomas, pancreatic cancer has one of the worst survival rates. Most patients will die of this cancer shortly after diagnosis, and currently, surgery is the only potential cure. Ductal adenocarcinoma is the most common histologic type. The search for prognostic parameters has progressed from mere physical or histomorphological tumor properties to molecular parameters. These, in turn, might point toward new therapeutic strategies. The K-ras oncogene is known to play a role in early stages of ductal adenocarcinoma carcinogenesis, and ras homologues are differentially expressed in cancerous versus normal ductal cells. RhoA belongs to a family of ras homologues comprising RhoA, RhoB, and RhoC. It is a guanosine triphosphatase associated with the cytoskeleton that seems to be involved in epithelial mesenchymal transition, a process of dedifferentiation. Immunohistologic RhoA expression was studied in a tissue microarray of 94 pancreatic ductal adenocarcinomas and correlated with clinicopathologic parameters and follow-up. RhoA protein expression, measured as labeling intensity or evaluated as percentage of reactive tumor cells, correlated with overall survival. A multivariate analysis demonstrated that RhoA protein expression is independent from other known prognostic parameters such as tumor size or grade. Moreover, a score combining RhoA expression with tumor size and grade resulted in a highly significant increase in the prognostic value for the overall survival of patients with pancreatic ductal adenocarcinoma.
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PMID:Prognostic significance of immunohistochemical RhoA expression on survival in pancreatic ductal adenocarcinoma: a high-throughput analysis. 1849 13

Pancreatic carcinoma is the fourth leading cause of death from cancer. Novel targets and therapeutic options are needed to aid in the treatment of pancreatic cancer. The compound UA62784 is a novel fluorenone with inhibitory activity against the centromere protein E (CENP-E) kinesin-like protein. UA62784 was isolated due to its selectivity in isogenic pancreatic carcinoma cell lines with a deletion of the DPC4 gene. UA62784 causes mitotic arrest by inhibiting chromosome congression at the metaphase plate likely through inhibition of the microtubule-associated ATPase activity of CENP-E. Furthermore, CENP-E binding to kinetochores during mitosis is not affected by UA62784, suggesting that the target lies within the motor domain of CENP-E. UA62784 is a novel specific inhibitor of CENP-E and its activity suggests a potential role for antimitotic drugs in treating pancreatic carcinomas.
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PMID:UA62784, a novel inhibitor of centromere protein E kinesin-like protein. 1913 11

Cardiac glycosides such as oleandrin are known to inhibit the Na,K-ATPase pump, resulting in a consequent increase in calcium influx in heart muscle. Here, we investigated the effect of oleandrin on the growth of human and mouse cancer cells in relation to Na,K-ATPase subunits. Oleandrin treatment resulted in selective inhibition of human cancer cell growth but not rodent cell proliferation, which corresponded to the relative level of Na,K-ATPase alpha3 subunit protein expression. Human pancreatic cancer cell lines were found to differentially express varying levels of alpha3 protein, but rodent cancer cells lacked discernable expression of this Na,K-ATPase isoform. A correlation was observed between the ratio of alpha3 to alpha1 isoforms and the level of oleandrin uptake during inhibition of cell growth and initiation of cell death; the higher the alpha3 expression relative to alpha1 expression, the more sensitive the cell was to treatment with oleandrin. Inhibition of proliferation of Panc-1 cells by oleandrin was significantly reduced when the relative expression of alpha3 was decreased by knocking down the expression of alpha3 isoform with alpha3 siRNA or increasing expression of the alpha1 isoform through transient transfection of alpha1 cDNA to the cells. Our data suggest that the relative lack of alpha3 (relative to alpha1) in rodent and some human tumor cells may explain their unresponsiveness to cardiac glycosides. In conclusion, the relatively higher expression of alpha3 with the limited expression of alpha1 may help predict which human tumors are likely to be responsive to treatment with potent lipid-soluble cardiac glycosides such as oleandrin.
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PMID:Oleandrin-mediated inhibition of human tumor cell proliferation: importance of Na,K-ATPase alpha subunits as drug targets. 1967 33


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