Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of manumycin, a competitive farnesyltransferase (FTase) inhibitor, on pancreatic cancer cell lines with or without K-ras mutation were studied. Manumycin inhibited the growth of human pancreatic cancer cells (SUIT-2, MIA PaCa-2, AsPC-1, BxPC-3) in a dose-dependent manner. The 50% inhibitory concentration (IC50) in cell lines with a mutant K-ras gene (SUIT-2, MIA PaCa-2, AsPC-1) was lower than that in BxPC-3 with a wild-type ras. Both mitogen-activated protein kinase activity after growth stimuli and the ability for chemotactic invasion were markedly more inhibited by manumycin in SUIT-2 than in BxPC-3. These results suggest that mutated Ras is more sensitive to manumycin than the wild type. Furthermore, tumor growth and liver metastasis in nude mice inoculated with manumycin-treated SUIT-2 cells were inhibited dose dependently. Inhibition of Ras activity might be a new anticancer strategy in pancreatic cancer in which Ras plays a role.
Pancreas 1997 Nov
PMID:Inhibition of growth and invasive activity of human pancreatic cancer cells by a farnesyltransferase inhibitor, manumycin. 936 Oct 92

Growth of the human pancreatic carcinoma cell line KP-1N was stimulated with cholecystokinin (CCK)-8. A 40% increase in cell numbers was observed in the presence of 10(-10) MCCK-8 and this increase was inhibited by the addition of 25 microM CCK-A receptor antagonist (CR1505). The binding affinity of CCK-8 to KP-1N cells was 21-fold higher than that of gastrin 17-I. No significant increase in intracellular Ca2+ concentration was found upon stimulation with CCK-8. Components of signal transduction pathways that were activated in KP-1N cells after stimulation with CCK-8 were studied. CCK-8 stimulated tyrosine phosphorylation of a mitogen-activated protein kinase (MAPK) of approximately 42 kDa (p42map). c-Jun amino-terminal kinases (JNKs) of 46 kDa (p46jnk) and 55 kDa (p55jnk) were also activated by CCK-8 and increased the phosphorylation of c-Jun. CCK-8 at 10(-7) M induced 1.5-fold increases in the phosphorylation of MAPK and of c-Jun by JNKs, respectively. These results suggest that cell proliferation stimulated with CCK-8 in KP-1N cells may be mediated by signal transduction cascades leading to activation of JNKs and MAPKs.
Pancreas 1998 May
PMID:Jun and MAP kinases are activated by cholecystokinin in the pancreatic carcinoma cell line KP-1N. 959 11

The dually phosphorylated c-jun kinase and p38 mitogen-activated protein (MAP) kinase, also termed stress kinases, are members of the MAP kinase family. They are activated early during cerulein pancreatitis induction and have been proposed as regulators during pancreatitis development by us and others. We recently showed that hyperthermia preconditioning induces expression of pancreatic heat-shock proteins (HSP) and protects against cerulein pancreatitis. Because it was further reported that HSP70 can prevent activation of stress kinases in lymphoid tumor cells, we investigated whether hyperthermia preconditioning might reduce hyperstimulation-mediated activation of pancreatic stress kinases. Pancreatic HSP expression was induced by whole-body hyperthermia preconditioning. Without prior HSP induction, cerulein led to a rapid and dose-dependent increase in serum lipase and amylase levels, pancreatic wet weight through edema formation, and activation of pancreatic MAP kinases. Hyperthermia preconditioning, although strongly inducing HSP70 and almost completely preventing edema formation, as well as the increase of serum amylase and lipase, did not reduce cerulein-mediated stress kinase activation. This indicates that in the pancreas, cerulein can strongly activate MAP kinases even when pancreatitis development is greatly inhibited, and that pancreatic HSPs do not inhibit activation of pancreatic stress kinases in vivo.
Pancreas 1999 Aug
PMID:Hyperthermia, inducing pancreatic heat-shock proteins, fails to prevent cerulein-induced stress kinase activation. 1043 62

Pancreatic carcinoma is characterized by poor prognosis and lack of response to conventional therapy for reasons that are not clear. Because of the structural relationship between the exocrine and endocrine pancreas and high concentrations of islet hormones bathing pancreatic tissue, we hypothesized that pancreatic cancer cell proliferation and glucose utilization are regulated by pancreatic islet hormones, particularly insulin. Based on this, the effect of islet hormones on pancreatic cancer cells in vitro was investigated. Five pancreatic cancer cell lines, CD11, CD18, HPAF, PANC-1, and MiaPaCa2 were used to investigate the effect of islet hormones on cell proliferation, glucose utilization, and GLUT-1 expression. Insulin, but not somatostatin and glucagon, induced pancreatic cancer cell growth in a concentration- and time-dependent manner. At concentrations within the range of those in the intrapancreatic vasculature, insulin (10(-10)-10(-8) mol/L) markedly increased [3H]-thymidine incorporation. Insulin significantly enhanced glucose utilization of pancreatic cancer cells before it enhanced cell proliferation. The MAPK kinase inhibitor PD 098059 abolished insulin-stimulated DNA synthesis and partially reduced insulin-stimulated glucose uptake. In contrast, the PI3 kinase inhibitor wortmannin substantially inhibited insulin-induced glucose uptake and partially blocked thymidine incorporation. Furthermore, after 24-hour treatment with insulin, GLUT-I expression in pancreatic cancer cells was markedly increased, indicating that insulin enhances glucose utilization partly through increasing glucose transport. These findings suggest that insulin stimulates proliferation and glucose utilization in pancreatic cancer cells by two distinct pathways. Insulin augments DNA synthesis mainly by MAP kinase activation and glucose uptake mainly by PI3 kinase activation and enhancement of GLUT-I expression. High intrapancreatic concentrations of insulin are likely to play an important role in stimulating pancreatic cancer growth indirectly by increasing substrate availability as well as by direct action as a trophic factor.
Pancreas 2000 Oct
PMID:Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression. 1103 77

It has been recently reported that kinases that belong to the mitogen-activated protein kinase (MAPK) family are rapidly activated by cholecystokinin (CCK) in rat pancreas both in vitro and in vivo. It is known that reactive oxygen species (ROS) play an important role in the pathogenesis of acute pancreatitis induced by supraphysiologic stimulation with CCK analogue, cerulein. The aim of our study was to evaluate whether MAPKs are activated by ROS in pancreatic acini. The activity of MAPK, c-Jun amino-terminal kinase (JNK), and p38 MAPK was determined in isolated rat pancreatic acinar cells by means of Western blotting, with the use of specific antibody that recognizes active, dually phosphorylated kinases. Incubation of acini with ROS donors, hydrogen peroxide (H2O2) and/or menadione (MND), strongly activated all three kinases. Activation of these kinases by ROS, but not by CCK, was substantially inhibited by pretreatment of acini with antioxidant N-acetylo-L-cysteine (NAC). Whereas CCK-induced activation of MAPK or JNK was totally or partially blocked by protein kinase C (PKC) inhibitor GF-109203X, ROS-induced activation of MAPK, JNK, and p38 MAPK was PKC independent. In conclusion, ROS strongly activate MAPK, JNK, and p38 MAPK in pancreatic acinar cells. It may be of importance in acute pancreatitis, because ROS are involved in the pathogenesis of this disease.
Pancreas 2000 Nov
PMID:Reactive oxygen species activate mitogen-activated protein kinases in pancreatic acinar cells. 1107 92

Pancreatic cancer is the fifth leading cause of cancer death in North America. Gemcitabine improves the quality of life of patients but fails to significantly reduce mortality. Our laboratory has demonstrated previously that the phosphatidylinositol 3'-kinase inhibitor wortmannin promotes gemcitabine antitumor activity (S. S. W. Ng et al., Clin. Cancer Res., 7: 3269-3275, 2001). The present study examined the effects of the epidermal growth factor receptor (EGFR) inhibitor OSI-774 ("Tarceva") alone and in combination with wortmannin and/or gemcitabine on downstream signaling molecules, as well as apoptosis in primary pancreatic cancer xenografts implanted orthotopically in severely combined immunodeficient mice. Tumors established from two pancreatic cancer patients [Ontario Cancer Institute Pancreas number (OCIP#) 2 and OCIP#7] were treated with various combinations of the above three drugs and harvested for analyses of the following: the levels of phosphorylated and nonphosphorylated forms of EGFR, protein kinase B (PKB/Akt) and extracellular-regulated kinase (ERK1/2), and the extent of apoptosis using immunofluorescence image analysis and TUNEL assay, respectively. OSI-774 alone significantly inhibited phosphorylation of EGFR in both of the primary xenografts. Phosphorylation of pERK decreased in OCIP#2, but not in OCIP#7. No significant effects on pPKB because of OSI-774 were observed in either tumor type. The extent of apoptosis was significantly increased by 2-fold in OCIP#2 tumors treated with gemcitabine and wortmannin in combination; an additional 2-fold increase in apoptosis was evident in the presence of OSI-774. Although wortmannin failed to enhance gemcitabine-induced apoptosis in OCIP#7 tumors, the extent of apoptosis was significantly increased with the inclusion of OSI-774 in the combination. Taken together, these findings support the use of OSI-774 plus a phosphatidylinositol 3'-kinase inhibitor in combination with gemcitabine in the treatment of pancreatic cancer.
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PMID:Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. 1249 10

Pancreatic ductal adenocarcinomas (PDACs) overexpress several members of the fibroblast growth factor (FGF) family of ligands and the type I FGF receptor (FGFR-1), and enhanced FGF-2 protein levels correlate with shorter postoperative survival of patients with PDAC. In this study, we investigated the effects of FGF-2 on cell proliferation and mitogen-activated protein kinase (MAPK) activation before and after abrogation of FGFR-1-dependent signaling in 4 pancreatic cancer cell lines (ASPC-1, COLO-357, MIA-PaCa-2, and PANC-1). Signaling was blocked by infecting the cells with an adenoviral vector encoding for a truncated FGFR-1 (AdtrFGFR-1). FGF-2 enhanced the growth of all 4 cell lines and activated MAPK in 3 of these cell lines. Infection with the AdtrFGFR-1 virus resulted in abundant expression of the truncated FGFR-1 at the RNA and protein level, markedly attenuated FGF-2-induced proliferation in all 4 tested cell lines, and decreased FGF-2-dependent MAPK activation in the 3 cell lines in which FGF-2 activated this pathway. These findings suggest that FGFR-1-mediated mitogenesis in multiple pancreatic cancer cells can be efficiently blocked with an adenoviral vector encoding a truncated FGFR-1, raising the possibility that AdtrFGFR-1 may ultimately have a therapeutic role in PDAC.
Pancreas 2004 Jan
PMID:Adenovirus-mediated transfer of a truncated fibroblast growth factor (FGF) type I receptor blocks FGF-2 signaling in multiple pancreatic cancer cell lines. 1470 26