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

Several peptide hormones have been shown to influence growth and function in pancreatic carcinoma and have given evidence for an autocrine feedback loop governing the proliferation of these malignant cells. Conversely, steroid hormones including glucocorticoids have been shown to inhibit the growth of pancreatic cancer cells; however, the prevalence of the glucocorticoid receptor or its mechanism of growth suppression in these tumors is unknown. The ability of growth factors thought to be active in this autocrine loop to reverse the glucocorticoid-induced growth inhibition was studied in vitro in a human pancreatic adenocarcinoma (HPAC) cell line with a well-characterized glucocorticoid receptor (GR). The glucocorticoid dexamethasone (DEX) inhibited growth in a dose-dependent manner as measured by a [3H]thymidine incorporation assay as well as an MTT cell proliferation assay. Maximal effects were seen within 48 hr at a concentration of 100 nM DEX, suppressing growth to approximately 18% of control. When the maximally suppressed DEX-treated cells were exposed to exogenous growth factors, they rapidly attained or exceeded the growth rate of control cells: insulin-like growth factor = 106%, transforming growth factor-alpha = 134%, insulin = 151%, and epidermal growth factor = 187% (all P < 0.05, Student's t test). In order to determine the frequency of the GR in pancreatic cancer and the clinical relevance of our findings, immunohistochemical staining for the GR was performed on 20 human tumors. Twelve (60%) of all cancers, as well as all normal pancreatic tissues (n = 4), stained positively for cytoplasmic and/or nuclear GR with expression correlating highly with degree of tumor differentiation (Kruskal-Wallis test, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Functional glucocorticoid receptor modulates pancreatic carcinoma growth through an autocrine loop. 751 83

The insulin-like growth factors (IGF-I and IGF-II) participate in the control of cell proliferation in normal and neoplastic lung cells. To examine the role of IGF binding proteins (IGFBPs) in modulating IGF actions in lung, we examined the production and regulation of IGFBPs from A549 cells, a human adenocarcinoma-derived lung cell line. Ligand blot and immunoblot analysis of conditioned media (CM) from A549 cells demonstrated IGFBP bands of relative molecular mass (M(r)) approximately 39-43,000 (IGFBP-3), 34,000 (IGFBP-2), 30,000 (IGFBP-1), and 24,000 (IGFBP-4). IGFBP-3 abundance in A549 cell CM increased following exposure to IGF-I and IGF-II (3.0- and 1.8-fold, respectively) without a change in IGFBP-3 transcript abundance, suggesting IGFBP-3 is post-transcriptionally regulated. Cycloheximide almost completely abrogated the IGF-I-stimulated increase in CM IGFBP-3, suggesting that ongoing protein synthesis is necessary for the IGF-I-stimulated increase in IGFBP-3 abundance. Increases in IGFBP-3 occurred by at least two mechanisms, through activation of the type 1 IGF receptor and by a type 1 IGF receptor independent mechanism. The increase in IGFBP-3 was due, in part, to activation of the type 1 IGF receptor because blocking type 1 IGF receptor activation with an antibody (alpha IR3) diminished the IGF-I-induced increase in IGFBP-3 and insulin, at doses that stimulate the type 1 IGF receptor, increased IGFBP-3 abundance. The increase in IGFBP-3 was partially independent of type 1 IGF receptor activation because [QAYL]-IGF-I, an analog of IGF-I that binds the type 1 IGF receptor but not IGFBP-3, was less potent than IGF-I in stimulating IGFBP-3 abundance, and IGF-II, which binds IGFBP-3 normally, but binds the type 1 IGF receptor with lower affinity than IGF-I, was nearly equipotent to IGF-I in its stimulation of IGFBP-3 accumulation at low concentrations. These results suggest that ligand binding decreases IGFBP-3 clearance or increases IGFBP-3 accumulation in CM. IGF-I decreased IGFBP-4 abundance in A549 cell CM without decreasing IGFBP-4 mRNA transcripts and without increasing the amount of cell-associated IGFBP-4. To determine whether the decrease in IGFBP-4 was due to increased degradation, cell-free CM was incubated with and without IGF-I, and IGFBP-4 abundance measured by ligand and immunoblot analyses.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Insulin-like growth factor-I (IGF-I) regulates IGFBP-3 and IGFBP-4 by multiple mechanisms in A549 human adenocarcinoma cells. 754 77

The activity of insulin-degrading enzyme (IDE), a thiol metalloprotease degrading insulin in many insulin target cells, was determined in human colon adenocarcinoma (Caco-2) cells. Insulin-degrading activity was localized in the cytosol of Caco-2 cells, accounting for 88% of total activity. Western blots and immunoprecipitation showed that IDE was present in the cytosol of Caco-2 cells and contributed to more than 93% cytosolic insulin-degrading activity. Cytosolic insulin degradation was strongly inhibited by IDE inhibitors, including N-ethylmaleimide, 1,10-phenanthroline, p-chloromericuribenzoate, and EDTA, but was not significantly or not as extensively inhibited by strong inhibitors of proteasome, i.e., chymostatin, soybean trypsin inhibitor, leupeptin, and Dip-F. These results suggest that IDE is present in Caco-2 cells, that Caco-2 IDE has properties similar to those of its counterparts in insulin-target tissues, and that it significantly contributes to intracellular insulin degradation.
 ...
PMID:Insulin-degrading enzyme in a human colon adenocarcinoma cell line (Caco-2). 759 85

The insulin-responsive R3230AC mammary tumor possesses type I and type II insulin-like growth factor (IGF) receptors, and membrane preparations display affinity cross-linking of 125I-labeled IGF-I to IGF-binding proteins (IGFBPs). To identify the IGFBPs produced, Northern blotting analysis of poly(A)+ RNA extracts from tumor tissue was performed. Although transcripts of IGFBP-1 were not detected, intense bands were obtained at 1.7 and 6 kilobases (kb) when hybridized with radiolabeled IGFBP-2 and IGFBP-5 cDNA probes, respectively. A 2.6-kb band and a 2.4-kb weaker band were observed after hybridization with IGFBP-3 and IGFBP-4 probes, respectively. When IGFBP-6 cDNA was used, two bands were seen: a higher mol wt band at 6.3 kb and a smaller one at 1.3 kb. Tumors from streptozotocin-induced diabetic rats displayed an increase in the expression of IGFBP-2, and insulin treatment for 3 days normalized the IGFBP-2 mRNA levels. Tumors from diabetic rats displayed no change in IGFBP-3, -4, -5, and -6 mRNA levels from tumors of normoglycemic rats. However, tumors from insulin-treated rats showed significantly higher levels of mRNA for IGFBP-4 and IGFBP-5 than tumors from normoglycemic or diabetic rats. A similar, but less pronounced, pattern of changes in IGFBP-3 mRNA was seen, whereas levels of IGFBP-6 mRNA were unchanged throughout. To identify the cell type producing the mRNAs for these IGFBPs, in situ hybridization of tissue sections was used. Procedures were established that localized three of the five IGFBPs expressed in this tumor tissue. This technique showed that IGFBP-3 mRNA transcripts were observed mainly in endothelial cells of tumor vasculature, although they were also detected in stromal cells, IGFBP-4 was present mainly in tumor stroma cells, and IGFBP-5 mRNA was expressed predominantly in the epithelial cells of this tumor. Expression of IGFBP-5 mRNA transcripts was significantly diminished in primary and long term cultured R3230AC cells grown in alpha-Minimum Essential Medium and 10% fetal bovine serum. Tumors arising from injection of long term cultured cells that were injected into isologous rats contained high amounts of mRNA transcripts for IGFBP-5, suggesting the presence, in vivo, of positive regulators for the expression of this BP. Tumor cells cultured in the presence of insulin displayed a 2.2- to 2.5-fold increase in the expression of IGFBP-5. These findings imply a role for insulin as a regulator of the expression of IGFBP-5 in the R3230AC adenocarcinoma.
 ...
PMID:Insulin-like growth factor-binding proteins in R3230AC mammary tumors of intact and diabetic rats. 769 88

Deregulation of growth in malignant cells has been suggested to be the result of increased secretion by these cells, of autocrine growth factors; alternatively, this deregulation has been assumed to be related to loss of sensitivity by malignant cells to secreted inhibitory molecules. The results of the present publication lend new support to both hypotheses. We recently showed that human prostate adenocarcinoma cells (PC-3 cells) secreted insulin-like growth factor binding proteins (IGFBP) of 45, 34 and 25 kDa. From medium conditioned by dense cultures of PC-3 cells, we have now purified two IGFBPs of M(r) 45 kDa and 34 kDa. The N-amino terminal sequences were determined, and it was shown that they are IGFBP-3. IGFBP-34 appeared to be a deglycosylated form of IGFBP-45. The two IGFBPs had more affinity for IGF-II than for IGF-I. IGFBP-45 and IGFBP-34 were growth-inhibitory factors of chick embryo fibroblasts (CEF): they totally inhibited DNA synthesis stimulated by serum in CEF. Our results point to a clear difference between the effects of these IGFBPs upon growth of normal prostate cells and malignant PC-3 cells. At a concentration of 150 ng/ml, they inhibited growth of normal prostate cells even in the presence of 1 microgram/ml insulin. This suggests that such inhibition was not simply the result of a decrease by the IGFBP of stimulation induced by serum IGF or IGF secreted by the cells. At a concentration of 150 ng/ml, IGFBP did not modify the growth of PC-3 cells. In contrast, it stimulated growth of PC-3 cells when added at a concentration lower than 50 ng/ml (about 1 nM). Our results thus provide new insight concerning the regulation of growth in PC-3 cells.
 ...
PMID:IGF binding protein-3 secreted by the prostate adenocarcinoma cells (PC-3): differential effect on PC-3 and normal prostate cell growth. 769 99

Surface-sterilized oocysts of Cryptosporidium parvum were applied to subconfluent monolayers of human adenocarcinoma (HCT-8) cells grown on coverslips in six-well cluster plates. Parasite-infected cultures were then incubated in RPMI 1640 with 10% fetal bovine serum, 15 mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) buffer, and antibiotics at 37 degrees C in a 5% CO2-95% air incubator for 2 h to allow sporozoites to excyst and enter cells. After cultures were washed free of debris, fresh cell culture media containing select supplements were added and cultures were reincubated. Parasite growth was assessed 66 h later by counting the number of parasite developmental stages in 25 random x 100 oil fields by Nomarski interference-contrast microscopy. Four vitamin supplements, calcium pantothenate, L-ascorbic acid, folic acid, and 4-(para)-aminobenzoic acid, each resulted in a significant increase in parasite numbers in vitro. The addition of insulin and the sugars glucose, galactose, and maltose also had a positive effect on parasite growth, although the effect was less pronounced than with any of the vitamins. Using the above information, we developed a supplemental medium formulation consisting of RPMI 1640 with 10% fetal bovine serum, 15 mM HEPES, 50 mM glucose, and 35 micrograms of ascorbic acid, 1.0 micrograms of folic acid, 4.0 micrograms of 4-aminobenzoic acid, 2.0 micrograms of calcium pantothenate, 0.1 U of insulin, 100 U of penicillin G, 100 micrograms of streptomycin, and 0.25 microgram of amphotericin B (Fungizone) per ml (pH 7.4). The growth of c. parvum in this medium was found to be enhanced approximately 10-fold compared with that in control medium without additional glucose, insulin, or vitamins.
 ...
PMID:Effects of select medium supplements on in vitro development of Cryptosporidium parvum in HCT-8 cells. 771 94

Caco-2 cell human colon adenocarcinoma cell line was used to study the hormonal regulation of small intestinal epithelial cell differentiation. We had previously shown that insulin-transferrin-selenium and triiodothyronine (5 x 10(-8) M)-supplemented medium can best replace serum after 2 days of culture for both the maintenance and differentiation of Caco-2 cells. The present study demonstrates that precoating petri dishes with complete serum allows the growth and differentiation of Caco-2 cells seeded directly in serum-free medium. On the other hand, precoating with dialyzed serum inhibits alkaline phosphatase and dipeptidyl-dipeptidase IV activities by more than 50%. The results obtained with complete serum-precoated culture plates indicate that there is no synergy between insulin and triiodothyronine because cells maintained in transferrin-selenium and triiodothyronine-supplemented medium, with or without insulin, express comparable enzyme activities. Moreover, large increases in alkaline phosphatase and dipeptidyl-dipeptidase IV activities were observed when triiodothyronine was added to the culture medium by the time confluency was reached. In contrast, gamma-glutamyltransferase was lowered to a greater extent when triiodothyronine was present from the beginning of culture. These findings show that triiodothyronine preferentially stimulates alkaline phosphatase and dipeptidyl-dipeptidase IV activities during the differentiation period whereas it selectively inhibits gamma-glutamyltransferase during the proliferation phase. Triiodothyronine acts in a dose-dependent manner.
 ...
PMID:Alkaline phosphatase and peptidase activities in Caco-2 cells: differential response to triiodothyronine. 788 29

There is now clear-cut evidence that polypeptide growth factors control the proliferation of the normal gastrointestinal mucosa. Epidermal growth factor (EGF) stimulates normal growth throughout the gastrointestinal tract, and accelerates the healing of ulcerated epithelium. While the effects of gastrin were at first thought to be similarly widespread, the gastrin target now appears to be restricted to the enterochromaffin-like cells in the stomach. Isolated reports suggest that several other hormones, including fibroblast growth factor and the insulin-like growth factors, have similar proliferative effects. In contrast, indirect evidence suggests that somatostatin and transforming growth factor-beta inhibit the growth of the gastrointestinal mucosa. The same growth factors profoundly affect the growth of some gastrointestinal carcinomas. Prolonged hypergastrinaemia increases the risk of development of gastric endocrine tumours, but has no effect on the incidence of gastric adenocarcinoma. Gastrin also stimulates the in vivo growth of 50% of gastric and colorectal carcinoma xenografts, but has no consistent effect on the growth of carcinoma cell lines in vitro. EGF, on the other hand, significantly stimulates proliferation of many gastrointestinal cell lines in culture. Interest has recently focused on autocrine stimulation of gastrointestinal carcinoma growth. Elevated levels of EGF receptor, and of EGF or related mRNAs, have been demonstrated in gastric carcinomas, and the growth of some gastrointestinal cell lines is inhibited by antibodies against EGF, and by antisense oligonucleotides based on EGF mRNA. Similarly gastrin/cholecystokinin antagonists inhibit the growth of several colon carcinoma cell lines, although the spectrum of antagonist potencies suggests that classical gastrin and cholecystokinin receptors are not necessarily involved. Continued research on antagonists may therefore lead to novel therapies for gastrointestinal cancers.
 ...
PMID:Gut hormones, growth and malignancy. 790 61

A series of benzylidenemalononitrile derivatives previously synthesized by condensing aromatic aldehydes with malononitrile derivatives are known as tyrphostins. In this study, 32 tyrphostins were synthesized, 19 of which are novel compounds. Both hydroxylated derivatives and compounds containing heteroaromatic moieties were prepared. We have confirmed and extended the observation that the tyrphostins displayed an enhancement in their ability to inhibit the epidermal growth factor (EGF) receptor tyrosine kinase domain as the number of hydroxyl groups on the aromatic portion was increased. IC50 values of 1-5 microM were readily achieved. Some inhibitory activity was seen with the heteroaromatic structures, with two compounds exhibiting IC50 values of 56 and 77 microM. However, these derivatives were poor inhibitors of the EGF receptor tyrosine kinase activity as compared to the hydroxylated derivatives. The ability of the 32 tyrphostins synthesized in the present study to inhibit proliferation of a human breast adenocarcinoma cell line (MCF-7) was determined using [3H]thymidine incorporation as a measure of DNA synthesis. Some of the compounds containing pyridine, imidazole or thiophene portions displayed antiproliferative activity comparable to that of tyrphostins prepared from 3,4,5-trihydroxybenzaldehyde. The lack of inhibitory effect of these heteroaromatic compounds on the EGF receptor tyrosine kinase activity suggests that their antiproliferative activity is not related to inhibition of EGF receptor function. As the growth of the MCF-7 cell line is governed by other factors, such as the insulin-like growth factors (IGFs) and oestradiol, it is also still to be established whether the antiproliferative activity of the hydroxylated tyrphostins is directly related to inhibition of the EGF receptor tyrosine kinase activity.
 ...
PMID:Synthesis and antiproliferative activity of tyrphostins containing heteroaromatic moieties. 791 98

The effects of insulin-like growth factor-1 (IGF-I), and a more potent variant LR3-IGF-I, which binds poorly to IGF-binding proteins, were investigated in rats bearing a mammary adenocarcinoma. The effect of insulin, either alone or in combination with LR3-IGF-I, was also investigated. Peptides were infused via osmotic minipumps for 6-7 days after tumour size reached 5% of body weight. Infusion of IGFs alone at either 200 or 500 microgram/day significantly decreased food intakes as well as circulating levels of insulin and glucose, and consequently failed to promote muscle protein accretion in the host. Tumour growth was increased by the IGFs, especially by LR3-IGF-I, even though these peptides did not promote growth of the adenocarcinoma in cell culture. Infusion of LR3-IGF-I, and to a lesser extent IGF-I, led to decreased rates of muscle protein synthesis and increased muscle protein breakdown, but each of these measures was closely related to the final tumour burden (r2 = 0.454 and 0.810 respectively; P < 0.01) and possibly resulted from a decrease in substrate supply to the host tissues. Insulin infusion (100 micrograms/day) increased food consumption by more than 50% and significantly decreased tumour growth. Insulin and LR3-IGF-I had a synergistic effect on host weight, which increased by 19.1 +/- 1.9, -1.1 +/- 4.7 and 37.9 +/- 1.5 g for insulin, LR3-IGF-I and combined treatments respectively. Carcass protein was increased by more than 10% with insulin treatment, due to increased rates of synthesis and decreased rates of muscle protein breakdown, but LR3-IGF-I had no positive effect on carcass protein accretion, either alone or in combination with insulin. Similarly, the amount of carcass fat was increased almost 2-fold by insulin treatment, whereas it was decreased by 30% by LR3-IGF-I. These changes may have arisen either from direct hormone effects on metabolism or from the indirect effects of food intake, or both. Our results suggest that IGF administration may exacerbate an insulin insufficiency associated with the tumour-bearing state and further decrease metabolic substrate supply to the host. This can be overcome by co-infusion of insulin.
 ...
PMID:Effects of insulin and insulin-like growth factors on protein and energy metabolism in tumour-bearing rats. 805 1


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>