Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001418 (adenocarcinoma)
 68,496 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the apoptotic signaling pathway which tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) induced, we investigated the contribution of reactive oxygen species (ROS), p38 mitogen-activated protein (MAP) kinase and caspases in human adenocarcinoma HeLa cells. Here we show that upon TRAIL/Apo2L exposure there was pronounced ROS accumulation and activation of p38 MAP kinase, and that activation of caspases and apoptosis followed. Pretreatment with antioxidants such as glutathione or estrogen attenuated TRAIL/Apo2L-induced apoptosis through a reduction of ROS generation and diminished p38 MAP kinase and caspase activation. The p38 MAP kinase inhibitor SB203580 prevented apoptosis through a blockage of caspase activation, although ROS generation was not attenuated. Furthermore, the pan-caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethyl ketone fully prevented apoptosis, while neither ROS accumulation nor p38 MAP kinase activation were affected. Therefore, our results suggest that TRAIL/Apo2L-induced apoptosis is mediated by ROS-activated p38 MAP kinase followed by caspase activation in HeLa cells.
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PMID:The involvement of reactive oxygen species (ROS) and p38 mitogen-activated protein (MAP) kinase in TRAIL/Apo2L-induced apoptosis. 1185 2

The novel cyclic hexadepsipeptide named pipalamycin was isolated from a culture filtrate of Streptomyces sp. ML297-90F8 as an apoptosis-inducing agent. The antibiotic was found to be consisting of each one mole of alanine, N-hydroxyalanine, glycine, N-acylated 3-hydroxyleucine, and two moles of piperazic acid. Pipalamycin induced apoptosis in apoptosis-resistant human pancreatic adenocarcinoma AsPC-1 cells at 0.3 microg/ml in 24 to approximately 48 hours. It also showed antibacterial activity on Gram-positive bacteria such as Staphylococcus aureus and Micrococcus luteus. Fermentation, isolation, structural elucidation and the biological activities of pipalamycin are described.
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PMID:Isolation of a novel cyclic hexadepsipeptide pipalamycin from Streptomyces as an apoptosis-inducing agent. 1191 58

Female transgenic FVB mice transfected with the mammary erbB-2/neu oncogene were injected 0.1 ml 0.9% solution of sodium chloride (control), 1 meg Vilon peptide (Lys-Glu) or Epitalon peptide (Ala-Glu-Asp-Glu), s.c., 5 days in succession once a month, beginning from the age of 2 months. The characteristics of mammary tumor induction in the control and experimental groups did not differ until the age of 9 months. Later on, Epitalon-treated mice revealed distinct inhibition of carcinogenesis. One tumor per animal was detected in 7% (control), 4% (Vilon) and 16% (Epitalon) (p < 0.05). Two or more tumors per animal were in 75%, 95% and 56%, respectively (p < 0.05). Largest diameter of mammary adenocarcinoma in the Epitalon group was smaller than in controls by 33% (p < 0.05). Although the number of mice with metastases to the lung in all three groups was practically identical, their incidence in the Vilon group was 2.6 times higher than in Epitalon-treated animals (p < 0.05). Largest diameter of metastasis in the Epitalon group was the smallest, too. Our data point to inhibition of mammary carcinogenesis by Epitalon in transgenic erbB-2/neu mice.
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PMID:[Effect of Epitalon and Vilon treatment on mammary carcinogenesis in transgenic erbB-2/NEU mice]. 1210 68

Female FVB/N HER-2/neu transgenic mice from the age of 2 months were subcutaneously injected with saline, the peptide Epitalon(R) (Ala-Glu-Asp-Gly) or with the peptide Vilon(R) (Lys-Glu) in a single dose of 1 microg/mouse for 5 consecutive days every month. Epitalon treatment reduced the cumulative number and the maximum size of tumors (p < 0.05). Furthermore, the number of mice bearing 1 mammary tumor was increased, whereas the number of mice bearing 2 or more mammary tumors was reduced in Epitalon-treated in comparison to saline-treated animals (p < 0.05). The size but not the number of lung metastases was reduced in Epitalon-treated compared to saline-treated mice (p < 0.05). The treatment with Vilon produced significant negative effects when compared to the control group, with an increased incidence of mammary cancer development (p < 0.05), a shorter mean latent period of tumors (p < 0.05) and an increased cumulative number of tumors (p < 0.05). A 3.7-fold reduction in the expression of HER-2/neu mRNA was found in mammary tumors from HER-2/neu transgenic mice treated with Epitalon compared to control animals. The expression of mRNA for HER-2/neu was also partially reduced in Vilon-treated mice, but it remained significantly higher in Vilon- than in Epitalon-treated animals (1.9-fold increase). The data demonstrate the inhibitory effect of Epitalon in the development of spontaneous mammary tumors in HER-2/neu mice, suggesting that a downregulation of HER-2/neu gene expression in mammary adenocarcinoma may be responsible, at least in part, for the antitumor effect of the peptide.
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PMID:Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. 1220 81

Ovine pulmonary adenocarcinoma, caused by jaagsiekte sheep retrovirus (JSRV), is a naturally occurring retrovirus-induced pulmonary neoplasm of sheep. We report here that expression of the JSRV env gene is sufficient to transform an avian embryo fibroblast cell line, DF-1. DF-1 cells transfected with an avian sarcoma-leukaemia retroviral expression vector containing the JSRV env gene [pRCASBP(A)-J:env] exhibited changes consistent with transformation, including contraction and rounding of cells with formation of dense foci. Transfection with a reporter construct expressing the green fluorescent protein did not induce morphological changes in DF-1 cells, eliminating the possibility that the vector, the transfection protocol or culturing techniques were responsible for the transformed phenotype. When pRCASBP(A)-J:env-transfected cells were inoculated into nude mice, tumours formed, verifying that the DF-1 cells were tumorigenic. Analysis of the JSRV env gene revealed a conserved tyrosine (597) and methionine (600) residue in the cytoplasmic tail within the transmembrane domain of the envelope, which creates a known binding site of SH2 domains in the p85 subunit of phosphatidylinositol 3-kinase. However, when this tyrosine residue was mutated to serine or alanine, transformation was not affected. Furthermore, mutation of the methionine residue to valine or leucine also failed to eliminate JSRV env-mediated transformation. These results are in contrast to mutational analysis performed in JSRV env-transformed murine NIH-3T3 cells in which both the tyrosine and methionine residues are necessary for transformation. These findings suggest that more than one mechanism may be involved in JSRV env-mediated transformation.
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PMID:The jaagsiekte sheep retrovirus envelope gene induces transformation of the avian fibroblast cell line DF-1 but does not require a conserved SH2 binding domain. 1238 9

(1) We have investigated the properties of native and haemagglutinin (HA)-tagged neuropeptide Y (NPY) Y(1) receptors after mutation of the palmitoylation site Cys(337) to Ser or Ala. (2) In Chinese hamster ovary cells expressing similar receptor levels, the C337A mutation abolished incorporation of [(3)H]palmitic acid into the HA-Y(1) receptor. (3) Cys(337) substitution did not alter the affinities of Y(1) receptor agonists or antagonists, but it eliminated the ability of guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) to displace [(125)I]PYY-specific binding (compared to approximately 50% inhibition in Y(1) or HA-Y(1) clones). (4) Stimulation of GTPgamma[(35)S] binding by native and HA-Y(1) receptors in standard incubation buffer (100 mM NaCl, 10 micro M GDP) was prevented by Cys(337) mutation. In this assay, the function of Y(1)(C337S) receptors could be partially rescued by reducing the Na(+) concentration, and when overexpressed (B(max): approximately 10 pmol mg(-1)), both HA-Y(1) and HA-Y(1)(C337A) receptors displayed similar responses to NPY and peptide YY (PYY). (5) In stably transfected adenocarcinoma cells expressing Y(1) or Y(1)(C337S) receptors, PYY inhibited anion secretion stimulated by vasoactive intestinal peptide (VIP; measured as short-circuit current, I(SC)) with similar potency (EC(50): 26-53 nM). In contrast to the transient Y(1) receptor-mediated responses observed at maximal PYY concentrations, I(SC) reductions in both Y(1)(C337S) clones were sustained. (6) We conclude that nonpalmitoylation of the Y(1) receptor reduces its coupling efficiency to G proteins, and may also indirectly influence desensitisation processes that depend on the formation of an active agonist-receptor conformation.
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PMID:Control of signalling efficacy by palmitoylation of the rat Y1 receptor. 1278 10

A sensitive and specific RP-HPLC assay was developed to measure the levels of polymorphonuclear elastase (PMN-E) activity in growing cell cultures. By combining a pre-incubation of the cells with a relatively non-toxic, PMN-E-specific inhibitor, MeOSuc-Ala-Ala-Pro-Val-chloromethylketone (MAAPVCK), the p-nitroaniline formed by the hydrolysis of the substrate MeOSuc-Ala-Ala-Pro-Val-p-NA by PMN-E is quantified. Elastase-like activity was measured in 14 human cells lines: 13 cancer cell lines (HL-60, U-937, A-427, LCLC-103H, YAPC, DAN-G, PA-TU-8902, KYSE-70, -510, -520, 5637, SISO and MCF-7) and one immortalized epithelial cell line (hTert-RPE1). Activity was detected in all lines; the lowest was found in hTert-RPE1 cells while the highest was detected in a pancreas adenocarcinoma line (PA-TU-8902). When the results were normalized according to cell volume instead of cell number, the leukemia line HL-60 had the highest activity and PA-TU-8902 ranked second. A 1 h pre-incubation with 9.0 microM of the irreversible PMN-E inhibitor MAAPVCK led to varying degrees of enzyme inhibition depending on the cell line; the strongest inhibition was observed with the PA-TU-8902 pancreatic cancer cell line (90% inhibition) while the weakest was seen with the A-427 lung cancer cell line (52%). These results indicate that PA-TU-8902 is a suitable in vitro model for testing the efficacy of PMN-E-activated prodrugs of antitumor agents.
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PMID:Quantification of elastase-like activity in 13 human cancer cell lines and in an immortalized human epithelial cell line by RP-HPLC. 1281 79

Overexpression of JNK binding domain inhibited glucose deprivation-induced JNK1 activation, relocalization of Daxx from the nucleus to the cytoplasm, and apoptosis signal-regulating kinase 1 (ASK1) oligomerization in human prostate adenocarcinoma DU-145 cells. However, SB203580, a p38 inhibitor, did not prevent relocalization of Daxx and oligomerization of ASK1 during glucose deprivation. Studies from in vivo labeling and immune complex kinase assay demonstrated that phosphorylation of Daxx occurred during glucose deprivation, and its phosphorylation was mediated through the ASK1-SEK1-JNK1-HIPK1 signal transduction pathway. Data from immunofluorescence staining and protein interaction assay suggest that phosphorylated Daxx may be translocated to the cytoplasm, bind to ASK1, and subsequently lead to ASK1 oligomerization. Mutation of Daxx Ser667 to Ala results in suppression of Daxx relocalization during glucose deprivation, suggesting that Ser667 residue plays an important role in the relocalization of Daxx. Unlike wild-type Daxx, a Daxx deletion mutant (amino acids 501-625) mainly localized to the cytoplasm, where it associated with ASK1, activated JNK1, and induced ASK1 oligomerization without glucose deprivation. Taken together, these results show that glucose deprivation activates the ASK1-SEK1-JNK1-HIPK1 pathway, and the activated HIPK1 is probably involved in the relocalization of Daxx from the nucleus to the cytoplasm. The relocalized Daxx may play an important role in glucose deprivation-induced ASK1 oligomerization.
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PMID:Role of the ASK1-SEK1-JNK1-HIPK1 signal in Daxx trafficking and ASK1 oligomerization. 1296 34

Few malignancies have frustrated the persistent efforts of the oncologist like pancreatic cancer. Pancreatic cancer is usually unresectable at the time of diagnosis because of metastasis or local extension. Despite the aggressive nature of this deadly disease, systemic treatment options are limited. Even the recent introduction of the deoxycytidine analogue gemcitabine does not extend median survival of responders beyond a year. Clearly, alternative, more effective regimens are needed for treating pancreatic carcinoma. In pancreatic cancer, there is overexpression of growth factors and growth factor receptors, including epidermal growth factor receptor (EGFR). Targeted toxins consist of a targeting polypeptide covalently linked to a peptide toxin. DAB(389)EGF is a fusion protein composed of the catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor (EGF). The authors have previously shown that DAB(389)EGF is selectively toxic to EGFR-overexpressing cells, including human brain tumour and lung carcinoma cell lines. Pancreatic adenocarcinoma should be responsive to this fusion protein based on its EGFR overexpression. However, the cytotoxic effect of DAB(389)EGF on human pancreatic carcinoma cell lines has yet to be explored. The authors describe preliminary data showing the potent cytotoxicity of DAB(389)EGF to human pancreatic carcinoma cell lines. Because of the nonspecific toxicity to liver and kidney (which possess EGFR) of systemic administration, they also propose a potential novel drug delivery system for direct toxin implantation into pancreatic tumours using endoscopic ultrasound guided fine-needle injection (EUS-FNI). Hopefully, the use of these targeted therapeutic approaches in combination with other modalities may further extend survival and quality of life in patients with pancreatic adenocarcinoma.
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PMID:Recombinant toxin DAB389EGF is cytotoxic to human pancreatic cancer cells. 1451 80

The Forkhead family transcription factor FKHRL1 is an inducer of apoptosis in its unphosphorylated form and was recently reported to be a substrate of Akt kinase. We studied the roles of FKHRL1 in both cisplatin-resistant Caov-3 (a papillary adenocarcinoma cell line) and cisplatin-sensitive A2780 human ovarian cancer cell lines. Treatment of Caov-3 cells but not A2780 cells with cisplatin transiently stimulated the phosphorylation of FKHRL1. Transfection experiments revealed that a kinase inactive-mutant of Akt or a triple mutant (TM) of FKHRL1, in which all three of the putative Akt phosphorylation sites were converted to alanine, was unable to phosphorylate the FKHRL1 protein in cells treated with cisplatin. Because the phosphorylated form of FKHRL1 is known to be localized in the cytoplasm, we examined whether cisplatin-induced phosphorylation of FKHRL1 might have an effect on the subcellular distribution of FKHRL1. Cisplatin induced the localization of FKHRL1 in the cytoplasm in Caov-3 cells but not in A2790 cells. Moreover, cisplatin induced the association of 14-3-3 protein with phosphorylated-FKHRL1 in Caov-3 cells but not in A2790 cells. Because the unphosphorylated form of FKHRL1 binds the Fas ligand promoter, thereby inducing apoptosis, we further examined the effect of the phosphorylation status of FKHRL1 on the activity of the Fas ligand promoter in the presence of cisplatin. Transfection with the kinase-inactive mutant of Akt or TM of FKHRL1 induced the activity of the Fas ligand promoter in Caov-3 cells. Moreover, exogenous expression of TM of FKHRL1 in Caov-3 cells decreased the cell viability after treatment with cisplatin. Our findings suggest that cisplatin causes the phosphorylation of FKHRL1 via a phosphatidylinositol 3-kinase/Akt cascade, and inhibition of this cascade sensitizes ovarian cancer cells to cisplatin.
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PMID:Inhibition of phosphorylation of a forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin. 1470 73


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