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

The proliferation and metabolism of H4IIE hepatoma cells is apparently mediated through the insulin receptor. These cells, however, also have high-affinity binding sites for insulin-like growth factor-I (IGF-I). Addition of insulin to H4IIE cells increased RNA synthesis, DNA synthesis and cell number. IGF-I, on the other hand, was ineffective at concentrations equivalent to the lowest effective insulin dose, although stimulation was observed with concentrations 100-fold higher. Similar results were obtained when glucose uptake was measured. Western blot analysis demonstrated that tyrosine phosphorylation patterns produced by insulin and IGF-I differed. In particular, phosphorylation of insulin receptor substrate-1 (IRS-1) was evident after treatment with insulin, but not after treatment with IGF-I. Correspondingly, insulin, but not IGF-I, stimulated receptor tyrosine kinase activity. In contrast with these results, both insulin and IGF-I induced mitogen-activated protein (MAP) kinase phosphorylation and activity at a concentration of 10 nM. The correlation between insulin-dependent and IGF-I-dependent MAP kinase activation was confirmed by Western blot analysis of phosphorylated MAP kinase kinase (MEK). These results suggest that phosphorylation of IRS-1 is essential for both cell proliferation and glucose metabolism, but is uncoupled from the MAP kinase cascade. Furthermore, stimulation of MEK and MAP kinase is independent of receptor tyrosine kinase activity.
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PMID:Insulin-like growth factor-I (IGF-I)-dependent activation of pp42/44 mitogen-activated protein kinase occurs independently of IGF-I receptor kinase activation and IRS-1 tyrosine phosphorylation. 1058 12

Leptin is a 16-kDa hormone secreted by adipocytes and plays an important role in control of feeding behavior and energy expenditure. In obesity, circulating levels of leptin and insulin are high because of the presence of increased body fat mass and insulin resistance. Recent reports have suggested that leptin can act through some of the components of the insulin signaling cascade, such as insulin receptor substrates (IRS-1 and IRS-2), phosphatidylinositol 3-kinase (PI 3-kinase), and mitogen-activated protein kinase, and can modify insulin-induced changes in gene expression in vitro and in vivo. Well differentiated hepatoma cells (Fao) possess both the long and short forms of the leptin receptor and respond to leptin with a stimulation of c-fos gene expression. In Fao cells, leptin alone had no effects on the insulin signaling pathway, but leptin pretreatment transiently enhanced insulin-induced tyrosine phosphorylation and PI 3-kinase binding to IRS-1, while producing an inhibition of tyrosine phosphorylation and PI 3-kinase binding to IRS-2. Leptin alone also induced serine phosphorylation of Akt and glycogen synthase kinase 3 but to a lesser extent than insulin, and the combination of these hormones was not additive. These results suggest complex interactions between the leptin and insulin signaling pathways that can potentially lead to differential modification of the metabolic and mitotic effects of insulin exerted through IRS-1 and IRS-2 and the downstream kinases that they activate.
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PMID:Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. 1068 12

The effects of a high concentration of glucose on the insulin receptor-down signaling were investigated in human hepatoma (HepG2) cells in vitro to delineate the molecular mechanism of insulin resistance under glucose toxicity. Treatment of the cells with high concentrations of glucose (15-33 mm) caused phosphorylation of serine residues of the insulin receptor substrate 1 (IRS-1), leading to reduced electrophoretic mobility of it. The phosphorylation of IRS-1 with high glucose treatment was blocked only by protein kinase C (PKC) inhibitors. The high glucose treatment attenuated insulin-induced association of IRS-1 and phosphatidylinositol 3-kinase and insulin-stimulated phosphorylation of Akt. A metabolic effect of insulin, stimulation of glycogen synthesis, was also inhibited by the treatment. In contrast, insulin-induced association of Shc and Grb2 was not inhibited. Treatment of the cells with high glucose promoted the translocation of PKCepsilon and PKCdelta from the cytosol to the plasma membrane but not that of other PKC isoforms. Finally, PKCepsilon and PKCdelta directly phosphorylated IRS-1 under cell-free conditions. We conclude that a high concentration of glucose causes phosphorylation of IRS-1, leading to selective attenuation of metabolic signaling of insulin. PKCepsilon and PKCdelta are involved in the down-regulation of insulin signaling, and they may lie in a pathway regulating the phosphorylation of IRS-1.
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PMID:Selective attenuation of metabolic branch of insulin receptor down-signaling by high glucose in a hepatoma cell line, HepG2 cells. 1076 99

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

Incubation of rat hepatoma Fao cells with insulin leads to a transient rise in Tyr phosphorylation of insulin receptor substrate (IRS) proteins. This is followed by elevation in their P-Ser/Thr content, and their dissociation from the insulin receptor (IR). Wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, abolished the increase in the P-Ser/Thr content of IRS-1, its dissociation from the IR, and the decrease in its P-Tyr content following 60 min of insulin treatment, indicating that the Ser kinases that negatively regulate IRS-1 function are downstream effectors of PI3K. PKCzeta fulfills this criterion, being an insulin-activated downstream effector of PI3K. Overexpression of PKCzeta in Fao cells, by infection of the cells with adenovirus-based PKCzeta construct, had no effect on its own, but it accelerated the rate of insulin-stimulated dissociation of IR.IRS-1 complexes and the rate of Tyr dephosphorylation of IRS-1. The insulin-stimulated negative regulatory role of PKCzeta was specific and could not be mimic by infecting Fao cells with adenoviral constructs encoding for PKC alpha, delta, or eta. Because the reduction in P-Tyr content of IRS-1 was accompanied by a reduced association of IRS-1 with p85, the regulatory subunit of PI3K, it suggests that this negative regulatory process induced by PKCzeta, has a built-in attenuation signal. Hence, insulin triggers a sequential cascade in which PI3K-mediated activation of PKCzeta inhibits IRS-1 functions, reduces complex formation between IRS-1 and PI3K, and inhibits further activation of PKCzeta itself. These findings implicate PKCzeta as a key element in a multistep negative feedback control mechanism of IRS-1 functions.
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PMID:Insulin stimulates PKCzeta -mediated phosphorylation of insulin receptor substrate-1 (IRS-1). A self-attenuated mechanism to negatively regulate the function of IRS proteins. 2975 17

Insulin resistance contributes to a number of metabolic disorders, including type II diabetes, hypertension, and atherosclerosis. Cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6, and hormones, such as growth hormone, are known to cause insulin resistance, but the mechanisms by which they inhibit the cellular response to insulin have not been elucidated. One mechanism by which these agents could cause insulin resistance is by inducing the expression of cellular proteins that inhibit insulin receptor (IR) signaling. Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling pathways, the expression of which is regulated by certain cytokines. SOCS proteins are therefore attractive candidates as mediators of cytokine-induced insulin resistance. We have found that SOCS-1 and SOCS-6 interact with the IR when expressed in human hepatoma cells (HepG2) or in rat hepatoma cells overexpressing the human IR. In SOCS-1-expressing cells, insulin treatment increases the extent of interaction with the IR, whereas in SOCS-6-expressing cells the association with the IR appears to require insulin treatment. SOCS-1 and SOCS-6 do not inhibit insulin-dependent IR autophosphorylation, but both proteins inhibit insulin-dependent activation of ERK1/2 and protein kinase B in vivo and IR-directed phosphorylation of IRS-1 in vitro. These results suggest that SOCS proteins may be inhibitors of IR signaling and could mediate cytokine-induced insulin resistance and contribute to the pathogenesis of type II diabetes.
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PMID:Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. 1134 31

Exogenous administration of eicosapentaenoic acid (EPA) improves insulin sensitivity, but its precise mechanism remains unknown. Here we show that EPA stimulates the intracellular insulin signaling pathway in hepatoma cells. Exposure of these cells to EPA caused up-regulation of several insulin-induced activities including tyrosine phosphorylation of insulin receptor substrate-1, insulin receptor substrate-1-associated phosphatidylinositol 3-kinase, and its downstream target Akt kinase activity as well as down-regulation of gluconeogenesis. In contrast, EPA decreased mitogen-activated protein kinase activity and inhibited cell proliferation. These findings raise the possibility that EPA up-regulates metabolic action of insulin and inhibits cell growth in humans.
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PMID:Dual action of eicosapentaenoic acid in hepatoma cells: up-regulation of metabolic action of insulin and inhibition of cell proliferation. 1139 Mar 73

Hyperhomocysteinemia and insulin resistance are independent factors for cardiovascular disease. Most of the angiotoxic effects of homocysteine are related to the formation of homocysteine thiolactone and the consequent increase in oxidative stress. The oxidative stress has also been shown to impair insulin action, therefore leading to insulin resistance. In order to study a putative direct effect of homocysteine on insulin signaling, we have characterized the molecular counter-regulation of the early events in the signal transduction of the insulin receptor, and the metabolic end-point of glycogen synthesis. We employed HTC rat hepatoma cells transfected with the human insulin receptor. A 10 min exposure to homocysteine thiolactone (50 microM) resulted in a significant inhibition of insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and its substrates IRS-1 and p60-70, as well as their association with the p85 regulatory subunit of phosphatidylinositol 3-kinase. These effects led to impairment of the insulin-stimulated phosphatidylinositol 3-kinase activity, which plays a central role in regulating insulin action. Thus, insulin-stimulated glycogen synthesis was also inhibited by homocysteine thiolactone. To investigate whether oxidative stress was mediating the counter-regulatory effect of homocysteine thiolactone on insulin signaling, we preincubated the cells (5 min) with 250 microM glutathione prior to the incubation with homocysteine (10 min) and subsequent insulin challenge. Glutathione completely abolished the effects of homocysteine thiolactone on insulin-receptor signaling and restored the insulin-stimulated glycogen synthesis. In conclusion, these data suggest that homocysteine thiolactone impairs insulin signaling by a mechanism involving oxidative stress, leading to a defect in insulin action.
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PMID:Homocysteine thiolactone inhibits insulin signaling, and glutathione has a protective effect. 1146 79

Insulin and insulin-like growth factor-1 (IGF-1) regulate metabolism and body growth through homologous receptor tyrosine kinases that phosphorylate the insulin receptor substrate (IRS) proteins. IRS-2 is an important IRS protein, as it mediates peripheral insulin action and beta-cell survival. In this study, we show that insulin, IGF-1, or osmotic stress promoted ubiquitin/proteasome-mediated degradation of IRS-2 in 3T3-L1 cells, Fao hepatoma, cells and mouse embryo fibroblasts; however, insulin/IGF-1 did not promote degradation of IRS-1 in 3T3-L1 preadipocytes or mouse embryo fibroblasts. MG132 or lactacystin, specific inhibitors of 26S proteasome, blocked insulin/IGF-1-induced degradation of IRS-2 and enhanced the detection of ubiquitinated IRS-2. Insulin/IGF1-induced ubiquitination and degradation of IRS-2 was blocked by inhibitors of phosphatidylinositol 3-kinase (wortmannin or LY294002) or mTOR (rapamycin). Chronic insulin or IGF-1 treatment of IRS-1-deficient mouse embryo fibroblasts inhibited IRS-2-mediated activation of Akt and ERK1/2, which was reversed by lactacystin pretreatment. By contrast, IRS-1 activation of Akt and ERK1/2 was not inhibited by chronic insulin/IGF-1 stimulation in IRS-2-deficient mouse embryo fibroblasts. Thus, we identified a novel negative feedback mechanism by which the ubiquitin/proteasome-mediated degradation of IRS-2 limits the magnitude and duration of the response to insulin or IGF-1.
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PMID:Regulation of insulin/insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2. 1154 73

Ghrelin was identified in the stomach as an endogenous ligand specific for the growth hormone secretagogue receptor (GHS-R). GHS-R is found in various tissues, but its function is unknown. Here we show that GHS-R is found in hepatoma cells. Exposure of these cells to ghrelin caused up-regulation of several insulin-induced activities including tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), association of the adapter molecule growth factor receptor-bound protein 2 with IRS-1, mitogen-activated protein kinase activity, and cell proliferation. Unlike insulin, ghrelin inhibited Akt kinase activity as well as up-regulated gluconeogenesis. These findings raise the possibility that ghrelin modulates insulin activities in humans.
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PMID:Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells. 1172 68


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