Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MAP kinase cascade-dependent responses were investigated during scattering of HepG2 human hepatoma cells stimulated by HGF or phorbol ester. Inhibition of phosphatidylinositol 3-kinase with LY294002 prevented completely the dissociation of cells. Inhibition of MAP kinase kinase (MEK) with PD98059 prevented the development of characteristic morphological changes associated with cell migration. EGF, which failed to induce cell scattering, caused a short-term increase in the phosphorylation of Erk1/Erk2 MAP kinases. On the contrary, HGF or phorbol ester stimulated the phosphorylation of MAP kinases for a long time. Experiments performed with LY294002 indicated that phosphatidylinositol 3-kinase contributed to the HGF-stimulated phosphorylation of Erk1/Erk2. This finding was confirmed by the demonstration that the MAP kinase cascade-dependent expression of a high-Mr (>300 kDa) protein pair appearing in the course of cell scattering was inhibited by LY294002 in HGF-induced cells but was not inhibited in phorbol ester-treated cells.
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PMID:Phosphatidylinositol 3-kinase contributes to Erk1/Erk2 MAP kinase activation associated with hepatocyte growth factor-induced cell scattering. 1065 96

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

Hepatocyte growth factor (HGF) is known to be a potent mitogen and motogen for epithelial cells. Hepatocellular carcinoma (HCC) often metastasizes, and the c-Met/HGF receptor is highly expressed by HCC cells. The aim of this study was to investigate the signaling pathways associated with the motogenic effect of HGF on HCC cells via c-Met. HCC cell lines (Hep3B, HepG2, PLC, and Huh-7) and HCC cells harvested from patients were used for the Boyden chamber assay of chemotactic activity as well as for immunoprecipitation and immunoblotting studies. HGF stimulated the motility of Hep3B, HepG2, and Huh-7 cells in a dose-dependent manner in association with tyrosine phosphorylation of c-Met and activation of phosphatidylinositol 3-kinase (PI3-K). A tyrosine kinase inhibitor (genistein) and a PI3-K inhibitor (wortmannin) prevented the migration of HCC cells. However, migration was not prevented by calphostin C, an inhibitor of protein kinase C (PKC), which is a downstream target of phospholipase Cgamma (PLCgamma). HGF also stimulated the migration of HCC cells obtained from three patients, while wortmannin prevented the migration of these cells. These results indicate that HGF stimulates the migration of HCC cells through the tyrosine phosphorylation of c-Met via activation of PI3-K.
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PMID:Hepatocyte growth factor promotes migration of human hepatocellular carcinoma via phosphatidylinositol 3-kinase. 1076 17

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

Liver injury during cholestasis reflects a balance between the effects of toxic and nontoxic bile acids. However, the critical distinction between a toxic and nontoxic bile acid remains subtle and unclear. For example, the glycine conjugate of chenodeoxycholate (GCDC) induces hepatocyte apoptosis, whereas the taurine conjugate (TCDC) does not. We hypothesized that the dissimilar cellular responses may reflect differential activation of a phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway. In the bile acid-transporting McNtcp.24 rat hepatoma cell line, TCDC, but not GCDC, stimulated PI3K activity. Consistent with this observation, inhibition of PI3K rendered TCDC cytotoxic, and constitutive activation of PI3K rendered GCDC nontoxic. Both Akt and the atypical protein kinase C isoform zeta (PKCzeta) have been implicated in PI3K-dependent survival signaling. However, TCDC activated PKCzeta, but not Akt. Moreover, inhibition of PKCzeta converted TCDC into a cytotoxic agent, whereas overexpression of wild-type PKCzeta blocked GCDC-induced apoptosis. We also demonstrate that TCDC activated nuclear factor kappaB (NF-kappaB) in a PI3K- and PKCzeta-dependent manner. Moreover, inhibition of NF-kappaB by an IkappaB super-repressor rendered TCDC cytotoxic, suggesting that NF-kappaB is also necessary to prevent the cytotoxic effects of TCDC. Collectively, these data suggest that some hydrophobic bile acids such as TCDC activate PI3K-dependent survival pathways, which prevent their otherwise inherent toxicity.
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PMID:The bile acid taurochenodeoxycholate activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. 1077 Sep 53

The protective adaptive response to electrophiles and reactive oxygen species is mediated by the enhanced expression of the phase II detoxifying genes through antioxidant response elements (AREs). The current study was designed to identify the signaling pathways responsible for the expression of rGSTA2 in response to cellular oxidative stress and to establish the molecular mechanistic basis. Deprivation of cystine and methionine caused oxidative stress in H4IIE hepatoma cells as evidenced by a marked decrease in the reduced glutathione (first order rate constant = 0.056 h(-1); t(1/2) = 12.6 h) and an increase in pro-oxidant production. Electrophoretic mobility shift assay revealed that the ARE complex, consisting of Nrf-1/2 and Maf proteins, was activated 12 to 48 h after sulfur amino acid deprivation (SAAD). The rGSTA2 mRNA level was elevated by SAAD beginning at 24 h, whereas the rGSTA2 subunit was maximally induced at 48 h. Nuclear ARE activation and rGSTA2 mRNA increase were both completely inhibited by wortmannin or LY294002, the phosphatidylinositol 3-kinase (PI3-kinase) inhibitors. The p38 mitogen-activated protein (MAP) kinase was activated at 0.5 to 3 h after SAAD, followed by sustained diminished activation up to 12 h. Inhibition of p38 MAP kinase by SB203580 prevented the ARE-mediated rGSTA2 induction. The activation of p38 MAP kinase, however, failed to be inhibited by wortmannin or LY294002, showing that PI3-kinase is not involved in the activation of p38 MAP kinase. Data showed that PI3-kinase plays an essential role in the ARE-mediated rGSTA2 induction by oxidative stress after SAAD, which activates the p38 MAP kinase and leads to rGSTA2 induction.
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PMID:The essential role of phosphatidylinositol 3-kinase and of p38 mitogen-activated protein kinase activation in the antioxidant response element-mediated rGSTA2 induction by decreased glutathione in H4IIE hepatoma cells. 1104 49

To elucidate the relationship between inositol lipid signal transduction and oncogenic transformation, the activity and subcellular distribution of phospholipase C isoforms and of phosphatidylinositol 3-kinase were analysed in Morris hepatoma cells, MH(1)C(1), with respect to normal rat liver cells. The results provide evidence of a gain of function of the enzymes involved in inositide signal transduction, the amount of which increased mainly at the nuclear level. Phospholipase C and phosphatidylinositol 3-kinase activities are significantly higher in rat hepatoma than in rat liver cells. Moreover, some phospholipase C isoforms are expressed at higher levels at the nuclear level; this is particularly evident in the case of the delta 1 isoform which is not expressed at the nuclear level in rat liver cells. Therefore, the autonomous nuclear signal transduction system, formerly reported as involved in the modulation of cell proliferation and differentiation, appears also affected in oncogenic transformation.
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PMID:Increased activity and nuclear localisation of inositol lipid signal transduction enzymes in rat hepatoma cells. 1111 55

Insulin modulates the biological actions of GH, but little is known about its effect on human hepatic GH receptors (GHRs). Using the human hepatoma cell line HuH7 as a model, we investigated insulin regulation of total, intracellular, and cell surface GHRs and receptor biosynthesis and turnover. Insulin up-regulated total and intracellular GHRs in a concentration-dependent manner. It increased surface GHRs in a biphasic manner, with a peak response at 10 nmol/L, and modulated GH-induced Janus kinase-2 phosphorylation in parallel with expression of surface GHRs. The abundance of GHR messenger ribonucleic acid and protein, as assessed by RT-PCR and Western analysis, respectively, markedly increased with insulin treatment. To examine whether insulin regulates GHRs at the posttranslational level, its effects on receptor surface translocation and internalization were investigated. Insulin suppressed surface translocation in a concentration-dependent manner, whereas internalization was unaffected. Moreover, insulin actions on total GHRs and surface translocation were inhibited by PD98059 and wortmannin, respectively. In conclusion, insulin regulates hepatic GHR biosynthesis and surface translocation in a reciprocal manner, with surface receptor availability the net result of the divergent effects. The divergent actions of insulin appear to be mediated by the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways, respectively.
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PMID:Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. 1113 33

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

The hepatitis B virus-X (HBx) protein is known as a multifunctional protein that not only coactivates transcription of viral and cellular genes but coordinates the balance between proliferation and programmed cell death, by inducing or blocking apoptosis. In this study the role of the HBx protein in activation of phosphatidylinositol 3-kinase (PI3K) was investigated as a possible cause of anti-apoptosis in liver cells. HBx relieved serum deprivation-induced and pro-apoptic stimuli-induced apoptosis in Chang liver (CHL) cells. Treatment with 1-d-3-deoxy-3-fluoro-myo-inositol, an antagonist to PI3K, which blocks the formation of 3'-phosphorylated phosphatidyl inositol in CHL cells transformed by HBx (CHL-X) but not normal Chang liver (CHL) cells, showed a marked loss of viability with evidence of apoptosis. Similarly, treatment with wortmannin, an inhibitor of PI3K, stimulated apoptosis in HBx-transformed CHL cells but not in normal cells, confirming that HBx blocks apoptosis through the PI3K pathway. The serine 47 threonine kinase, Akt, one of the downstream effectors of PI3K-dependent survival signaling was 2-fold higher in HBx-transformed CHL (CHL-X) cells than CHL cells. Phosphorylation of Akt at serine 473 and Bad at serine 136 were induced by HBx, which were specifically blocked by wortmannin and dominant negative mutants of Akt and Bad, respectively. We also demonstrated that HBx inhibits caspase 3 activity and HBx down-regulation of caspase 3 activity was blocked by the PI3K inhibitor. Regions required for PI3K phosphorylation on the HBx protein overlap with the known transactivation domains. HBx blocks apoptosis induced by serum withdrawal in CHL cells in a p53-independent manner. The results indicate that, unlike other DNA tumor viruses that block apoptosis by inactivating p53, the hepatitis B virus achieves protection from apoptotic death through a HBx-PI3K-Akt-Bad pathway and by inactivating caspase 3 activity that is at least partially p53-independent in liver cells. Moreover, these data suggest that modulation of the PI3K activity may represent a potential therapeutic strategy to counteract the occurrence of apoptosis in human hepatocellular carcinoma.
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PMID:The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. 1127 72


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