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Biomedical subjects

M Korc

Publications and source records attributed to M Korc.

194 records · Page 11Linked to original sources
PubMed1981

Regulation of protein synthesis in normal and diabetic rat pancreas by cholecystokinin.

The effects of cholecystokinin (CCK) on [3H]leucine incorporation into protein were studied in isolated pancreatic acini from normal and streptozotocin-induced diabetic rats. CCK8, the biologically active C-terminal octapeptide of CCK, increased [3H]leucine incorporation into protein over a concentration range that stimulates digestive enzyme secretion (1 X 10(-11) to 1 X 10(-10) M); at higher concentrations, CCK8 inhibited incorporation. Stimulation of [3H]leucine incorporation was greatest in acini from diabetic rats, intermediate in acini from fed normal rats, and least in acini from fasted rats. The magnitude of inhibition was similar in all acini. A significant stimulatory effect of CCK8 in acini from diabetic rats was detected after 10 min and was maximal after 40 min of incubation. Carbachol mimicked both the stimulatory and inhibitory effects of CCK, whereas the Ca2+ ionophore A23187 mimicked only the inhibitory effects. Insulin also stimulated [3H]leucine incorporation in acini from diabetic rats, and its effects were additive to the stimulatory effect of CCK. The present findings suggest that physiological concentrations of CCK and other pancreatic secretagogues may participate in the regulation of pancreatic protein synthesis.

Amino Acids↗
PubMed1981

Receptors for cholecystokinin and insulin in isolated pancreatic acini: hormonal control of secretion and metabolism.

Both isolated pancreatic cells and isolated pancreatic acini have been prepared from mouse and rat pancreas. Although isolated cells are useful for the study of early events in stimulus-secretion coupling such as regulation of Ca2+ fluxes, they show a relatively poor ability to secrete digestive enzymes in response to secretagogues. Most likely this deficiency in secretion is due to the loss of specialization at the luminal plasma membrane surface. In contrast to isolated cells, isolated pancreatic acini can be used to study the secretion of digestive enzymes in response to hormones and neurotransmitters. Using isolated acini and a new preparation of radioiodinated cholecystokinin (CCK), we have been able to characterize pancreatic CCK receptors. Analysis of binding data reveals two orders of binding sites, a high affinity site (Kd = 64 pm) and a low affinity site (Kd = 21 nm). Stimulation of amylase release correlates with occupancy of the high affinity site. High affinity receptors for insulin are also present on isolated acini. After binding to these receptors, insulin stimulates protein and amylase synthesis. Insulin does not directly stimulate amylase secretion but rather potentiates the effects of hormonal secretagogues. These studies indicate, therefore, that isolated pancreatic acini can be employed to study in vitro various events in hormonal and neurotransmitter regulation of pancreatic enzyme secretion and metabolism.

Animals↗
PubMed1979

Stimulation of the glucose transport system in isolated mouse pancreatic acini by cholecystokinin and analogues.

Cholecystokinin and analogues increased the uptake of 2-deoxy-D-glucose and 3-O-methylglucose into isolated mouse pancreatic acini. This uptake was mediated by a facilitated glucose transport system that was saturable, stereospecific, and was inhibited by both phloretin and cytochalasin B. In agreement with previous studies of acinar function, caerulein was more potent and pentagastrin less potent than cholecystokinin in increasing sugar transport. The cholinergic analogue carbachol mimicked the effect of caerulein; atropine completely abolished the effects of carbachol but was without influence on the effects of the polypeptide hormones. In contrast, secretion, as well as dibutyryl cyclic AMP and dibutyryl cyclic GMP, had no effect on 2-deoxy-D-glucose uptake. Two lines of evidence suggested that hormonal stimulation of this sugar transport system was related to mobilization of cellular Ca2+. First, depletion of cellular Ca2+ by incubation of acini with ethylene glycol bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) reduced the effect of caerulein. Second, the Ca2+ ionophore A23187 mimicked the effects of caerulein on 2-deoxy-D-glucose uptake when Ca2+ was present in the medium.

Amylases↗
PubMed1978

Action of secretagogues on a new preparation of functionally intact, isolated pancreatic acini.

Isolated pancreatic acini were prepared by a new method from mouse and rat pancreases by digestion with purified collagenase and chymotrypsin followed by mechanical shearing. Acini were structurally similar to those of the intact pancreas, having a normal luminal structure but with the basal acinar cell membranes exposed to the incubation medium. Amylase release in response to both cholinergic analogues and the cholecystokinin analogues caerulein and pentagastrin was comparable to that of the intact pancreas, but was much greater than previously reported for isolated acinar cells. Cholinergic-stimulated release was inhibited by atropine with a Ki value of 1.4 nM which is comparable to other muscarinic receptors. All agonists tested, when added at supramaximal concentrations, produced a submaximal release of amylase even though ATP levels and the release of slowly exchanging 45Ca2+ were normal or increased. Acini releasing amylase submaximally after being exposed to supramaximal concentrations of carbachol failed to respond to a maximal amount of caerulein or to the Ca2+ ionophore A23187. It is concluded that the decreased response (desensitization) is a postreceptor phenomenon and possibly mediated by Ca2+ itself.

Adenosine Triphosphate↗
PubMedDate not supplied

Potential role of the epidermal growth factor receptor in human pancreatic cancer.

The epidermal growth factor (EGF) receptor is a transmembrane protein that has tyrosine kinase activity. It is activated by both EGF and transforming growth factor-alpha (TGF-alpha). Human pancreatic cancer cells overexpress the EGF receptor and exhibit a parallel increase in EGF receptor mRNA without a detectable increase in the number of gene copies coding for the receptor. These cells also produce TGF-alpha and are capable of binding exogenous TGF-alpha. They often recycle EGF, but markedly and rapidly degrade TGF-alpha. However, TGF-alpha is 10-100-fold more potent than EGF in enhancing their anchorage-independent growth. Both growth factors induce EGF receptor down-regulation, but EGF is more efficient than TGF-alpha in this regard. The concomitant overexpression of the EGF receptor and production of TGF-alpha, the recycling of EGF, and the attenuated ability of TGF-alpha to down-regulate the EGF receptor may combine to provide a distinct growth advantage to human pancreatic cancer cells.

Epidermal Growth Factor↗
PubMedDate not supplied

Processing and transfer of epidermal growth factor in developing rat jejunum and ileum.

Using everted sac technique we demonstrated the transfer of 125I-mEGF across the jejunal and ileal walls of suckling, weanling and adult rats. The transfer by the suckling rat jejunum and ileum was significantly inhibited by the presence of dinitrophenol and sodium azide or by the replacement of sodium with potassium or choline, RP-HPLC analysis detected carboxy-terminal processing of 125I-mEGF in suckling and adult rat jejunum and ileum. Suckling rat jejunum produced 125I-des(53)mEGF and 125I-des(49-53)mEGF, whereas 125I-des(48-53)mEGF was detected in suckling rat ileum or adult rat jejunum and ileum. All three forms of 125I-mEGF bound to anti-EGF antibody and EGF receptors. The receptor binding of 125I-des(53)mEGF was higher than that of 125I-mEGF, but those of 125I-des(49-53)mEGF and 125I-des(48-53)mEGF were greatly diminished. Results indicate a carboxy-terminal processing of mouse EGF during uptake and transfer in the small intestine of developing and adult rats, and the resulting products showed altered receptor binding. An identical amino acid sequence of the C-terminal pentapeptide of eGF from mouse, human and possibly rat may suggest a biological significance of C-terminal processing of EGF in the small intestine.

Animals↗
PubMedDate not supplied

Bak expression and cell death occur in peritumorous tissue but not in pancreatic cancer cells.

Bak is a pro-apoptotic member of the Bcl-2 family whose genes are involved in regulation of programmed cell death. Using in situ hybridization, immunohistochemistry, and Northern blot analysis, we studied the expression of Bak in specimens from 12 normal pancreata and 26 primary pancreatic cancers, and correlated the findings with the clinical and histopathologic data of the patients. By comparison with normal pancreas, Northern blot analysis demonstrated a 2.5-fold increase of Bak messenger RNA expression in the tumor samples (P <0. 001). Elevated levels were found in 15 of the 26 pancreatic cancer tissue specimens. In these samples Bak expression was increased 4.3 fold (P <0.001). No association was detected between Bak expression and tumor stage. In situ hybridization and immunohistochemistry revealed that the tumor cells themselves and the stroma cells expressed only low levels of Bak. In contrast, in regions adjacent to the tumor, which showed chronic inflammation, there was always high expression in the acinar and inflammatory cells, explaining the increased Bak levels found in the tumor samples by means of Northern blot analysis. In the normal pancreas the expression of Bak was generally moderate in the acinar cells and low in the ductal and islet cells. In situ analysis using the terminal deoxynucleotidyl transferase method further showed that there was extensive cell death in the peritumorous areas with chronic inflammation. Taken together, these results suggest that in pancreatic cancer Bak expression and programmed cell death are present in cells that are localized in regions of chronic inflammation surrounding the pancreatic cancer cells but not in the tumor cells themselves, a situation that may facilitate tumor growth and spread.

Adolescent↗
PubMedDate not supplied

Increased cyclin D1 in human pancreatic cancer is associated with decreased postoperative survival.

Cyclin D 1 belongs to a family of protein kinases that have been implicated in cell cycle regulation. In the present study we characterized cyclin D1 expression in 6 cultured human pancreatic cancer cell lines and in normal and cancerous human pancreatic tissues. A 4.4-kb cyclin D1 mRNA transcript was present in all cell lines and in all pancreatic tissues. Cyclin D1 mRNA levels were 2.1-fold higher in the pancreatic cancers than in normal pancreatic tissues (p < 0.0002). Cancer patients with lower cyclin D1 levels (n=16) had a median survival of 15.5 months whereas patients with higher levels (n=16) had a median survival of 6.5 months (p < 0.007). These data indicate that cyclin D1 expression may serve as a predictor of postoperative survival in pancreatic cancer patients, and raise the possibility that treatment modalities blocking cyclin D1 activity may have a future role in the therapy of these patients.

Adult↗
PubMedDate not supplied

Pancreatic cancer cells express interleukin-13 and -4 receptors, and their growth is inhibited by Pseudomonas exotoxin coupled to interleukin-13 and -4.

BACKGROUND: Interleukin (IL)-13 and -4 are multifunctional cytokines that bind to specific cell-surface receptors. The aim of this study was to determine whether pancreatic cancer cells express either receptor, and to assess the growth suppressive effects of chimeric proteins composed of a Pseudomonas exotoxin (PE) A mutant (PE38QQR) fused to IL-13 (IL-13-PE38QQR) or IL-4 (IL-4-PE38QQR) in these cells. MATERIALS AND METHODS: Northern and Western blot analysis were used to analyze the expression of IL-4/-13 receptors and the common gamma chain (gamma c) in pancreatic cancer cell lines. MTT growth assays were carried out to assess the effects of IL-4/-13 and IL-4/-13-PE38QQR on cell growth. RESULTS: All 6 pancreatic cancer cell lines examined expressed IL-13R alpha 1 and IL-4R alpha, one cell line expressed IL-13R alpha 2, and 5 pancreatic cancer cell lines expressed gamma c. IL-13 (5 nM) significantly enhanced the growth of 3 cell lines, whereas IL-4 (5 nM) enhanced the growth of 1 cell line. In contrast, IL-13-PE38QQR and IL-4-PE38QQR inhibited the growth of all 6 tested cell lines. There were large variations in the individual sensitivity of the cells, with LD50 values ranging from 100 ng/ml to 5 micrograms/ml for IL-13-PE38QQR and from 20 ng/ml to 10 micrograms/ml for IL-4-PE38QQR. IL-13 and -4 antagonized these inhibitory activities in some, but not all, of the cell lines. CONCLUSIONS: IL-13 and -4 may act as mitogens toward pancreatic cancer cells by activating IL-4- and IL-13-receptors and IL-13- and IL-4-coupled toxins may ultimately have a role in the treatment of pancreatic cancer.

ADP Ribose Transferases↗
PubMedDate not supplied

Chronic pancreatitis: pathogenesis and molecular aspects.

Chronic pancreatitis (CP) is characterized by irreversible morphological and functional alterations of the pancreas presenting clinically with upper abdominal pain as well as exocrine and endocrine insufficiencies. CP is morphologically characterized by pancreatic head enlargement, calcifications of the parenchyma, cysts, and pancreatic stones. The most common etiological factor of CP in Western industrialized countries is alcohol abuse; less common factors include hereditary pancreatitis, CP due to metabolic disturbances, CP due to pancreas divisum or duodenal wall cysts, and idiopathic CP. The molecular alterations leading to the chronic inflammatory process are nor completely understood. Research during the last years, however, has elucidated that a number of growth factors and their receptors are overexpressed in CP, which is thought to contribute to the high degree of pancreatic fibrosis and to the proliferative potential of ductular cells in this disorder. In addition, gene mutations have been detected in a subgroup of CP samples underscoring the pre-malignant potential of CP. In this review we will summarize our current knowledge about pathogenic and molecular aspects of CP.

Chronic Disease↗
PubMedDate not supplied

p53 expression in human pancreatic cancer correlates with enhanced biological aggressiveness.

Immunohistochemical analysis of the p53 tumor suppressor gene was performed in 69 human pancreatic ductal adenocarcinomas, using a highly specific anti-p53 antibody. Nuclear immunoreactivity was found in 40 tumors, yielding an overall frequency of 58%. Immunoblotting confirmed that nuclear immunoreactivity was associated with increased p53 protein levels. p53 mRNA levels were increased in 9 of 9 tested cancers, without evidence for gene amplification. Analysis of the immunostaining data by chi-square and log-rank indicated that the presence of nuclear immunoreactivity correlated with a more advanced clinical stage, and a statistically significant decrease in the post-operative survival period. In 12 cancers, metastatic tissue samples were also available for p53 analysis. Nuclear p53 immunostaining in the primary tumors was not always associated with p53 immunoreactivity in the metastatic samples, and metastases occurred in the absence of nuclear p53 immunoreactivity in the primary lesion. These findings suggest that increased p53 protein levels in human pancreatic cancer may be due not only to p53 mutations which attenuate the degradation of the protein but also to an increase in p53 mRNA levels leading to increased p53 synthesis, and that p53 nuclear immunoreactivity in these cancers implies enhanced tumor aggressiveness but is not essential for the development of metastases.

Antibody Specificity↗
PubMedDate not supplied

Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness.

Immunohistochemical analysis for the epidermal growth factor receptor (EGFR), EGF and transforming growth factor-alpha (TGF-alpha) was performed in 87 human pancreatic carcinomas. Expression frequencies for EGFR, EGF, and TGF-alpha were 43%, 46% and 54%, respectively. Coexpression of the receptor and at least one of its ligands occurred in 38% of the tumors, and correlated with large tumor size, advanced clinical staging, and decreased survival period. In situ hybridization revealed that the respective mRNAs were also overexpressed in the carcinomas. These findings suggest that coexpression of EGFR and its ligands may contribute to the aggressiveness of human pancreatic cancer.

Adult↗