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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-stimulated signaling pathways are activated upon interactions between the intracellular domains of the receptor and its downstream effectors. Insulin receptor substrate proteins (IRS-1, -2, -3 and -4) are the best-studied substrates for the insulin receptor kinase (IRK). We have previously shown that IRS-1 and IRS-2 interact with the juxtamembrane (JM) but not with the carboxyl-terminal (CT) region of the insulin receptor (IR) in vitro. However, the precise role of these IR regions in mediating insulin's bioeffects is still unresolved. In the present work we made use of vaccinia virus as a vector for quantitative expression of the JM and CT domains within the cytoplasm of physiologically insulin-responsive primary rat adipocytes and rat hepatoma Fao cells. We could demonstrate that overexpression of either the JM or the CT domains did not inhibit either insulin binding or insulin-stimulated receptor autophosphorylation. In contrast, metabolic effects such as insulin-induced glucose utilization in adipocytes, and insulin-induced amino acid utilization in Fao hepatoma cells were inhibited (70-80%) in cells overexpressing the JM but not the CT domains of IR. The inhibitory effects of the overexpressed JM domain were accompanied by inhibition of insulin-stimulated IRS-1 phosphorylation, decreased IRS-1-associated PI3K activity, and decreased phosphorylation of the downstream effectors of PI3K, PKB and p70 S6K. Insulin-stimulated thymidine incorporation in Fao cells was also inhibited (40%) upon overexpression of the JM but not the CT region of IR. Our findings suggest that interactions between the JM region of IR and its downstream effectors are obligatory for insulin-stimulated metabolic functions in physiologically relevant insulin responsive cells. They also rule out the possibility that interaction of proteins, including PI3K, with the CT domain can provide an alternative pathway.
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PMID:The juxtamembrane but not the carboxyl-terminal domain of the insulin receptor mediates insulin's metabolic functions in primary adipocytes and cultured hepatoma cells. 1082 35

Insulin regulates the expression of several hepatic genes. Although the general definition of insulin signaling has progressed dramatically, the elucidation of the complete signaling pathway from insulin receptor to transcription factors involved in the regulation of a specific gene remains to be established. In fact, recent works suggest that multiple divergent insulin signaling pathways regulate the expression of distinct genes. 5-Aminolevulinate synthase (ALAS) is a mitochondrial matrix enzyme that catalyzes the first and rate-limiting step of heme biosynthesis. It has been reported that insulin caused the rapid inhibition of housekeeping ALAS transcription, but the mechanism involved in this repression has not been explored. The present study investigates the role of phosphatidylinositol 3-kinase (PI3-kinase) and mitogen-activated protein kinase pathways in insulin signaling relevant to ALAS inhibition. To explore this, we combined the transient overexpression of regulatory proteins involved in these pathways and the use of small cell permeant inhibitors in rat hepatocytes and HepG2 cells. Wortmannin and LY294002, PI3-kinase inhibitors, as well as lovastatin and PD152440, Ras farnesylation inhibitors, and MEK inhibitor PD98059 abolished the insulin repression of ALAS transcription. The inhibitor of mTOR/p70(S6K) rapamycin had no effect whatsoever upon hormone action. The overexpression of vectors encoding constitutively active Ras, MEK, or p90(RSK) mimicked the inhibitory action of insulin. Conversely, negative mutants of PKB, Ras, or MEK impaired insulin inhibition of ALAS promoter activity. Furthermore, inhibition of one of the pathways blocks the inhibitory effect produced by the activation of the other. Our findings suggest that factors involved in two signaling pathways that are often considered to be functionally separate during insulin action, the Ras/ERK/p90(RSK) pathway and the PI3K/PKB pathway, are jointly required for insulin-mediated inhibition of ALAS gene expression in rat hepatocytes and human hepatoma cells.
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PMID:Phosphatidylinositol 3-kinase and Ras/mitogen-activated protein kinase signaling pathways are required for the regulation of 5-aminolevulinate synthase gene expression by insulin. 1171 32

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric DNA-binding complex of the subunits alpha and beta with relevance in O(2) and energy homeostasis. The labile component, HIF-1alpha, is not only activated by hypoxia but also by peptides such as insulin and interleukin-1 (IL-1) in normoxia. We investigated whether inhibitors of mitogen-activated protein kinase kinases (MAPKKs: PD 98059, U0126) and phosphatidylinositol 3-kinase (PI3K: LY 294002) do not only lower the hypoxia-induced, but also the insulin- and IL-1-induced HIF-1alpha accumulation and HIF-1 DNA-binding in human hepatoma cell cultures (line HepG2). The results show that LY 294002 suppressed HIF-1 activation in a dose-dependent manner irrespective of the stimulus. With respect to target proteins controlled by HIF-1, the production of erythropoietin was fully blocked and that of vascular endothelial growth factor reduced following inhibition of the PI3K pathway. The role of MAPKKs in this process remained in question, because PD 98059 and U0126 did not significantly reduce HIF-1alpha levels at non-toxic doses. We propose that PI3K signaling is not only important in the hypoxic induction of HIF-1 but it is also crucially involved in the response to insulin and IL-1.
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PMID:Normoxic induction of the hypoxia-inducible factor 1alpha by insulin and interleukin-1beta involves the phosphatidylinositol 3-kinase pathway. 1185 72

Phosphatidylethanolamine N-methyltransferase 2 (PEMT2) is an isoform of PEMT that converts phosphatidylethanolamine to phosphatidylcholine in mammalian liver. Overexpression of PEMT2 led to inhibition of proliferation of hepatoma cells [J. Biol. Chem. 269 (1994) 24531]. The present study aims to unravel the molecular mechanism of the reduced proliferation, especially the signaling transducer proteins involved in this process. Thus, we chose PI3K/Akt pathway that is initiated by growth factors and leads to cell survival and proliferation. Rat hepatoma CBRH-7919 cells transfected with pemt2-cDNA showed that: (1) signaling proteins including c-Met, PDGF receptor, PI3K, Akt and Bcl-2 all had reduced expression as shown by Western blotting studies; (2) flow cytometric and DNA ladder assays showed that 22.9% of the pemt2-transfected cells were undergoing apoptosis; (3) the activity of Akt was decreased as shown by Western blotting using antibody directed against p-Akt (Thr308); (4) wortmannin and PD98059, inhibitors of PI3K and MEK, respectively, both inhibited Akt activity, indicating that PI3K and MAPK pathways were merging at Akt in CBRH-7919 cells. The above results suggest that overexpression of PEMT2 strongly downregulated the PI3K/Akt signaling pathway at multiple sites and induced apoptosis. This, at least partly, explains the molecular mechanism of impaired proliferation induced by pemt2 transfection.
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PMID:Overexpression of PEMT2 downregulates the PI3K/Akt signaling pathway in rat hepatoma cells. 1196 Jul 51

Manumycin was reported to have inhibitory effect on farnesyltransferase by competing with the farnesyl pyrophosphate substrate. It exhibited different antiproliferative activity in human hepatocellular carcinoma HepG2 cells, primary cultured human cardiac muscle cells and human liver cells (CLC). HepG2 cells overexpressing ras gene were more sensitive to manumycin than the other cells. The difference might be related to Ras protein levels in these cell lines. Manumycin reduced the amount of functional ras localized at the cytoplasmic membrane, resulting in blocked C-raf-1 assocation with Ras. Manumycin inhibited ERK1/2 phosphorylation in HepG2 cells without reduced expression of ERK1/2 protein. The levels of protein MKP-1 were significantly up-regulated. Our study also demonstrated that manumycin inhibited p85/PI3K and Akt phosphorylation without reduced expression of p85/PI3K and Akt, and interfered with the association of p85/PI3K and Ras. These findings indicated that manumycin interfered with Ras membrane localization, shut down the downstream pathways of Ras and inhibited cell proliferation in HepG2 cells.
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PMID:Manumycin inhibits cell proliferation and the Ras signal transduction pathway in human hepatocellular carcinoma cells. 1273 20

The effect of insulin on cancer metastatic potential was studied in a human hepatocarcinoma cell line, H7721. Cell adhesion to human umbilical vein endothelial cells (HUVECs) and laminin as well as chemotactic cell migration and invasion were selected as the indices of metastasis-related phenotypes for assessment of metastatic potential ex vivo. The results indicated that insulin enhanced all of these metastasis-related phenotypes. After the cells were treated with specific inhibitor of PI3K (LY294002) or transfected with antisense cDNA of PKB (AS-PKB), all of the above phenotypes were attenuated, and they could not be significantly stimulated by insulin, indicating that the insulin effect on metastatic potential was mediated by PI3K and PKB. Only the monoclonal antibody to the sialyl Lewis X (SLe(x)), but not antibodies to other Lewis antigens, significantly blocked the cell adhesion to HUVECs, cell migration and invasion, suggesting that SLe(x) played a crucial role in the metastatic potential of H7721 cells. The upregulation of cell surface SLe(x) and alpha-1,3-fucosyltransferase-VII (alpha-1,3 Fuc T-VII, enzyme for SLe(x) synthesis) was also mediated by PI3K and PKB, since LY294002 and AS-PKB also reduced the expressions of SLe(x) and alpha-1,3 FucT-VII, and attenuated the response to insulin. Furthermore, the alterations in the expressions of PKB protein and activity were correlated to the changes of metastatic phenotypes and SLe(x) expression. Taken together, the insulin/PKB signalling pathway participated in the enhancement of metastatic potential of H7721 cells, which was mediated by the upregulation of the expression of SLe(x) and alpha-1,3 FucT-VII.
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PMID:Insulin/protein kinase B signalling pathway upregulates metastasis-related phenotypes and molecules in H7721 human hepatocarcinoma cell line. 1295 Feb 63

Liver tumor cells arise from normal hepatocytes that escape negative control of proliferation. The transcription factor C/EBPalpha maintains quiescence of hepatocytes through two pathways: inhibition of cdks and repression of E2F. Nevertheless, liver tumors and cultured hepatoma cell lines proliferate in the presence of C/EBPalpha. In this paper, we present evidence that the activation of the PI3K/Akt pathway in liver tumor cells blocks the growth inhibitory activity of C/EBPalpha through the PP2A-mediated dephosphorylation of C/EBPalpha on Ser 193, leading to a failure of C/EBPalpha to interact with and inhibit cdks and E2F. Mutation of Ser 193 to Ala also abolishes the ability of C/EBPalpha to cause growth arrest because of a lack of interactions with cdk2 and E2F-Rb complexes. These data provide a molecular basis for the development of liver tumors in which the activation of PI3K/Akt pathway neutralizes C/EBPalpha growth inhibitory activity.
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PMID:Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP alpha growth inhibitory activity. 1510 4

Development of radiation resistance is one of the major reasons that cancer cells do not respond to radiotherapy and the mechanism for resistance is still not clear. Two sublines of human hepatocellular carcinoma Hep G2 cells were established from cells that survived two different irradiation regimes, 2 Gy for 10 days or 10 Gy for 2 days, respectively. Using MTT assay, the radiation conditioned cells were found to be more resistant to gamma-irradiation and have a greater extent of potentially lethal damage repair (PLDR) for radiation than the parent cells. By Western blot analysis, the radiation-conditioned cells were found to overexpress Raf-1 which is known to regulate the radiation resistance of cells. Inhibition of Raf-1 expression by antisense oligonucleotides increased the radiation sensitivity of the radiation-conditioned cells while inhibitors of Ras (L744,832), PI3K (LY294002) and p38 (SB203580) had no effect. Moreover, antisense Raf-1 oligonucleotides also decreased the radiation induced PLDR capacity of the radiation conditioned cells. It is therefore suggested that Raf-1 may induce radiation resistance through an increase in radiation induced PLDR capacity in Hep G2 cells.
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PMID:The role of Raf-1 in radiation resistance of human hepatocellular carcinoma Hep G2 cells. 1554 62

Insulin action is impaired in diabetic patients, which leads to increased hepatic glucose production. Plants and herbs have been used for medicinal purposes, including the treatment of diabetes, for centuries. Since dietary management is a starting point for the treatment of diabetes, it is important to recognize the effect of plant-based compounds on tissues that regulate glucose metabolism, such as the liver. In a recent study, several herbs and spices were found to increase glucose uptake into adipocytes, an insulin-like effect. Our data reveal that Syzygium aromaticum (L.) Merrill and Perry (Myrtaceae) (commonly referred to as clove) extract acts like insulin in hepatocytes and hepatoma cells by reducing phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) gene expression. Much like insulin, clove-mediated repression is reversed by PI3K inhibitors and N-acetylcysteine (NAC). A more global analysis of gene expression by DNA microarray analysis reveals that clove and insulin regulate the expression of many of the same genes in a similar manner. These results demonstrate that consumption of certain plant-based diets may have beneficial effects for the treatment of diabetes and indicate a potential role for compounds derived from clove as insulin-mimetic agents.
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PMID:An extract of Syzygium aromaticum represses genes encoding hepatic gluconeogenic enzymes. 1558 82

Growth hormone (GH) and insulin are important regulators of cellular and whole body metabolism as well as somatic growth and body composition. Studies have indicated complex feedback effects of GH on insulin action and of insulin on GH signaling pathways. Previous studies in our laboratory have shown that GH induction of signal transducers and activators of transcription (STAT)5B tyrosine phosphorylation is inhibited by prolonged insulin treatment, probably via downregulation of GHR. Here, we find that in rat H4IIE hepatoma cells GH-induced tyrosine phosphorylation of two other STATs (STAT3 and STAT1) was also greatly reduced following prolonged insulin pretreatment compared with that induced by GH alone. In the present work, total STAT5B and STAT1 protein levels were not altered by prolonged insulin treatment. However, prolonged insulin treatment (16 h; 10 or 100 nM) resulted in a 30-40% reduction of total STAT3 protein, with little change at 0.1 and 1.0 nM insulin. Thus, there is a selective reduction of total STAT3 protein levels by insulin, but only at high concentration of insulin. Basal tyrosine phosphorylated (PY)-STAT3 was also significantly reduced by prolonged insulin treatment, and to a greater extent than total STAT3 protein levels. The inhibitory effect of insulin on total STAT3 protein and basal PY-STAT3 levels was dependent on activation of the MEK-ERK pathway, rather than the PI3K pathway. In contrast, the MEK-ERK pathway did not play a major role in insulin's inhibition of GH-induced PY-STAT3 and PY-STAT1. The present studies indicate that prolonged hyperinsulinemia, such as that found in some obese patients or patients with Type 2 diabetes mellitus, may have profound effects on GH signaling via STAT3 and STAT1.
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PMID:Prolonged insulin treatment inhibits GH signaling via STAT3 and STAT1. 1574 7


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