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

Human hepatitis C virus (HCV) is the leading cause of chronic hepatitis, which often results in liver cirrhosis and hepatocellular carcinoma. The HCV RNA genome codes for at least ten proteins. The HCV non-structural protein 5A (NS5A) has generated considerable interest due to its effect on interferon sensitivity via binding and inactivating the cellular protein kinase, PKR. It has been shown that NS5A engages in the endoplasmic reticulum (ER)-nucleus signal transduction pathway. The expression of NS5A in the ER induces an ER stress ultimately leading to the activation of STAT-3 and NF-kappaB. This pathway is sensitive to inhibitors of Ca(2+) uptake in the mitochondria (ruthenium red), Ca(2+) chelators (TMB-8, EGTA-AM), and antioxidants (PDTC, NAC, Mn-SOD). The inhibitory effect of protein tyrosine kinase (PTK) inhibitors indicates the involvement of PTK in NF-kappaB activation by NS5A. This implicates an alternate pathway of NF-kappaB activation by NS5A. The actions of NS5A have also been studied in the context of an HCV subgenomic replicon inducing a similar intracellular event. Thus, activation of NF-kappaB leads to the induction of cellular genes, which are largely antiapoptotic in function. These studies suggest a potential function of NS5A in inducing chronic liver disease and hepatocellular carcinoma associated with HCV infection.
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PMID:Endoplasmic reticulum (ER) stress: hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-kappaB and STAT-3. 1241 55

Arsenic is a toxic metalloid known to interact with drug-metabolizing enzymes. In the present study, we investigated the effects of arsenic trioxide (As2O3), recently used as an anticancer drug, on the expression of human cytochrome P450 (P450) 1A1, which bioactivates polycyclic aromatic hydrocarbons into mutagenic metabolites. Clinically relevant concentrations (0.25-5 microM) of As2O3 were demonstrated to inhibit CYP1A activity in primary human hepatocytes and hepatoma Hep3B and HepG2 cells coexposed to 3-methylcholanthrene (3MC), benzo(a)pyrene, or dioxin and the metalloid for 24 h. Inhibition reached 50 and 90% in Hep3B cells treated with 1 and 5 microM As2O3, respectively, and was not due to direct interaction of the metalloid with CYP1A1. As2O3 (2.5-5 microM) was demonstrated to markedly reduce induction of CYP1A1 mRNA and apoprotein levels and gene promotor activity in 3MC-treated Hep3B cells, whereas lower concentrations (0.25-1 microM) were ineffective. These effects of As2O3 were abrogated by N-acetylcysteine. Surprisingly, this agent was found 1) to block cellular arsenic uptake when coincubated with the metalloid and 2) to increase arsenic efflux through multidrug resistance-associated proteins. In addition, blockade of these transporters was shown to enhance intracellular amounts of metalloid and to potentiate its effects on CYP1A1 gene. Finally, our results have demonstrated that As2O3, at low concentrations routinely reached in As2O3-treated patients, prevents induction of human CYP1A1 gene expression and that such an effect is increased by blocking multidrug resistance-associated proteins.
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PMID:Blockage of multidrug resistance-associated proteins potentiates the inhibitory effects of arsenic trioxide on CYP1A1 induction by polycyclic aromatic hydrocarbons. 1249 May 85

Hypoxia in tumors is generally associated with chemoresistance and radioresistance. However, the correlation between the heterodimeric hypoxia-inducible factor-1 (HIF-1) and the multidrug resistance transporter P-glycoprotein (P-gp) has not been investigated. Herein, we demonstrate that with increasing size of DU-145 prostate multicellular tumor spheroids the pericellular oxygen pressure and the generation of reactive oxygen species decreased, whereas the alpha-subunit of HIF-1 (HIF-1alpha) and P-gp were up-regulated. Furthermore, P-gp was up-regulated under experimental physiological hypoxia and chemical hypoxia induced by either cobalt chloride or desferrioxamine. The pro-oxidants H2O2 and buthionine sulfoximine down-regulated HIF-1alpha and P-gp, whereas up-regulation was achieved with the radical scavengers dehydroascorbate, N-acetylcysteine, and vitamin E. The correlation of HIF-1alpha and P-gp expression was validated by the use of hepatoma tumor spheroids that were either wild type (Hepa1) or mutant (Hepa1C4) for aryl hydrocarbon receptor nuclear translocator (ARNT), i.e., HIF-1beta. Chemical hypoxia robustly increased HIF-1alpha as well as P-gp expression in Hepa1 tumor spheroids, whereas no changes were observed in Hepa1C4 spheroids. Hence, our data demonstrate that expression of P-gp in multicellular tumor spheroids is under the control of HIF-1.
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PMID:Regulation of the multidrug resistance transporter P-glycoprotein in multicellular tumor spheroids by hypoxia-inducible factor (HIF-1) and reactive oxygen species. 1251 19

Glucose depletion results in cellular stress and reactive oxygen species (ROS) production, which evokes adaptive and protective responses. One such protective response is the induction of haem oxygenase 1 (HO-1), which catalyses the rate-limiting step in haem degradation, liberating iron, CO and biliverdin. The present study evaluated the role of ROS and the mitochondrial electron-transport chain in the induction of HO-1 by glucose deprivation in HepG2 hepatoma cells. Either N-acetylcysteine, an antioxidant, or deferoxamine, an iron chelator, resulted in a dose-dependent inhibition of HO-1 mRNA and protein induction during glucose deprivation, suggesting a redox- and iron-dependent mechanism. Inhibitors of electron-transport chain complex III, antimycin A and myxothiazol, the ATP synthase inhibitor oligomycin and ATP depletion with 2-deoxyglucose or glucosamine also blocked HO-1 induction. To address the involvement of ROS further, specifically H(2)O(2), we showed that overexpression of catalase completely blocked HO-1 activation by glucose deprivation. In contrast, inhibition of nuclear factor kappa B, mitogen-activated protein kinase (MAPK), protein kinase A, protein kinase C, phosphoinositide 3-kinase, cyclo-oxygenase or cytosolic phospholipase A(2), did not prevent HO-1 induction. These results demonstrate that activation of the HO-1 gene by glucose deprivation is mediated by a 'glucose metabolic response' pathway via generation of ROS and that the pathway requires a functional electron-transport chain.
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PMID:Haem oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain. 1258 63

Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have been reported to exert anti-inflammatory activities in macrophages by competition for transcriptional coactivators with some transcriptional factors, including NF-kappaB. In the present study the influence of PPARgamma activators on IFN-gamma-elicited macrophage stimulation and signaling cascades was investigated. The results show that IFN-gamma-induced inducible NO synthase (iNOS) gene transcription, iNOS protein induction, and NO production are more sensitive to inhibition by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) than by the other two PPARgamma agonists, GW1929 and ciglitazone. Delayed addition of 15dPGJ(2) for 2 h resulted in reduced inhibition, suggesting action by 15dPGJ(2) on the upstream signaling cascades. Immunoblotting, DNA binding, and reporter gene assays consistently revealed the inhibitory ability of 15dPGJ(2), but not GW1929 or ciglitazone, on IFN-gamma-elicited signaling cascades, including tyrosine phosphorylation of Janus tyrosine protein kinase 2 and STAT1, DNA binding, and IFN regulatory factor-1 trans-activation of STAT1. These effects of 15dPGJ(2) were not abrogated by the PPARgamma antagonist, bisphenol A diglycidyl ether, indicating the PPARgamma-independent actions. 15dPGJ(2) also attenuated IL-6-induced tyrosine phosphorylation of STAT1 and STAT3 in Hep3B hepatoma cells. Consistent with the inhibitory effect of reactive oxygen species on STAT1 signaling, STAT1 inhibition by 15dPGJ(2) was abrogated by N-acetylcysteine, glutathione, superoxide dismutase, and catalase. Furthermore, 15dPGJ(2)-induced inhibition of STAT1 phosphorylation and NO production still occurred in the presence of peroxovanadate, ruling out the action mechanism of 15dPGJ(2) on tyrosine phosphatase. Taken together, for the first time in this study we demonstrate that 15dPGJ(2) can inhibit cytokine-stimulated Janus kinase 2-STAT signaling through a PPARgamma-independent, reactive oxygen species-dependent mechanism. These data provide a novel molecular mechanism of iNOS inhibition by 15dPGJ(2) and confirm its physiological role in anti-inflammation.
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PMID:Inhibition of IFN-gamma-mediated inducible nitric oxide synthase induction by the peroxisome proliferator-activated receptor gamma agonist, 15-deoxy-delta 12,14-prostaglandin J2, involves inhibition of the upstream Janus kinase/STAT1 signaling pathway. 1284 70

P-Glycoprotein (P-gp) encoded by the MDR gene is one of the main factors in multidrug resistance. Its expression in cancer cells, which compromises cancer outcome, can be enhanced by some stress signals. Energy depletion, frequently observed in malignant cells, was shown to induce chemoresistance and could be one of these signals. To test this hypothesis, we studied the effect of glucose deprivation on P-gp expression in a rat hepatoma cell line (Fao). Incubation of Fao cells with a glucose-free medium enhanced P-gp mRNA and protein expression in a time-dependent manner, up to 400% at 40 h. This effect was associated with a stimulation of [(3)H]vinblastine efflux by P-gp despite impaired glycosylation. It was reproduced by inducers of endoplasmic reticulum stress response, such as 2-deoxyglucose (DG), tunicamycin, and thapsigargin. P-gp mRNA induction by DG was preceded by an increase in activator protein binding activity, c-Jun expression, and phosphorylation. In contrast, nuclear factor-kappaB binding activity was unaffected by DG. The antioxidant N-acetylcysteine partially reversed the increase in P-gp mRNA and protein levels induced by DG, as well as the enhancement of c-Jun phosphorylation and activator protein binding activity. Finally, transient transfection of the cells with a deleted mutant of c-Jun, Tam 67, abolished the DG-induced P-gp mRNA expression and mdr1b promoter activation. In conclusion, glucose deprivation enhances P-gp expression and transport function in liver cancer cells. This effect is mediated by endoplasmic reticulum stress response and involves MDR transcriptional induction through c-Jun activation. These results emphasize the importance of glucose metabolism in chemoresistance.
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PMID:Glucose depletion enhances P-glycoprotein expression in hepatoma cells: role of endoplasmic reticulum stress response. 1461 25

To evaluate the suppressive effects of nuclear factor kappa B (NF-kappaB) inhibitors on metastasis, three agents, pentoxifylline (PTX, 0.5% in diet), N-acetyl-L-cysteine (NAC, 0.5% in diet), and aspirin (ASP, 0.5% in diet) were applied in an in vivo highly metastatic rat hepatocellular carcinoma (HCC) model in F344 male rats. Administration of NF-kappaB inhibitors for 8 weeks after induction of highly metastatic HCC by sequential treatment with diethylnitrosamine and N-nitrosomorpholine did not cause any significant change in survival rate or body weight. The incidence of HCC was 100% at week 23, regardless of treatment with NF-kappaB inhibitors. PTX, NAC, and ASP did not exert any significant effect on the development or differentiation of HCCs, although PTX tended to decrease the multiplicity of HCC. Although no lung metastasis was observed in the rats killed at the end of the period of carcinogen exposure, lung metastasis was found in 100% of animals in all the groups at the end of the experiment. Multiplicity of lung metastasis was significantly decreased by PTX and NAC, whereas ASP was without significant influence. The size of metastatic nodules was also significantly reduced in the PTX treatment group. Furthermore, the inhibitory kappa-B (IkappaB) protein level, considered to be a marker for the degree of NF-kappaB transcription, was significantly suppressed by PTX. mRNA expression in HCC for vascular cell adhesion molecule-1 (VCAM-1), which is considered to play a key role in attachment of cancer cells to the endothelium, was significantly suppressed by PTX. Among the splicing variants of VEGF, VEGF-A120, VEGF-A144, VEGF-A164, and VEGF-A188, suppressed mRNA expression of VEGF-A188 appeared to be correlated with suppression of lung metastasis formation. In conclusion, the present study demonstrated that NF-kappaB inhibitors have the potential to inhibit lung metastasis from rat HCCs in vivo, and PTX is especially promising. Its mechanism of action may involve suppression of VCAM-1 and VEGF-A188 production.
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PMID:Suppression of metastasis by nuclear factor kappaB inhibitors in an in vivo lung metastasis model of chemically induced hepatocellular carcinoma. 1472 Mar 22

Shikonin has been demonstrated to exhibit anti-cancer activity, but the underlying mechanisms are poorly understood. In this report, we showed that the administration of shikonin could result in the induction of apoptotic cell death of human hepatoma cell line, SK-Hep-1. As evident by the flow-cytometric studies, shikonin has the capability of generating increased amounts of intracellular reactive oxygen species (ROS) during the early stage of this apoptotic process (ca. one-hour), and subsequently accompanied by the dissipation of mitochondrial transmembrane potential (deltapsi (m)) at 3 hours. Further studies indicated that this apoptotic process could effectively be protected by the pretreatment of shikonin-treated cells with glutathione (GSH) and N-acetylcysteine (NAC), a precursor of GSH, but not by cyclosporin A (CyA), an inhibitor of mitochondrial permeability transition (MPT) pore. These data further proved that ROS-mediated oxidative stress was the pivotal element involved in the induction of apoptosis of SK-Hep-1 cells. Taken together, we suggest that shikonin-induced apoptosis of SK-Hep-1 cells proceeds by an oxidative stress-mediated pathway.
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PMID:Involvement of reactive oxygen species, but not mitochondrial permeability transition in the apoptotic induction of human SK-Hep-1 hepatoma cells by shikonin. 1475 28

Hepatitis C virus (HCV) is a positive-stranded RNA virus that causes severe liver diseases, such as cirrhosis and hepatocellular carcinoma. HCV uses an RNA-dependent RNA polymerase to replicate its genome and an internal ribosomal entry site to translate its proteins. HCV infection is characterized by an increase in the concentrations of reactive oxygen species (ROS), the effect of which on HCV replication has yet to be determined. In this report, we investigated the effect of ROS on HCV replication, using a bicistronic subgenomic RNA replicon and a genomic RNA that can replicate in human hepatoma cells. The treatment with peroxide at concentrations that did not deplete intracellular glutathione or induce cell death resulted in significant decreases in the HCV RNA level in the cells. This response could be partially reversed by the antioxidant N-acetylcysteine. Further studies indicated that such a suppressive response to ROS was not due to the suppression of HCV protein synthesis or the destabilization of HCV RNA. Rather, it occurred rapidly at the level of RNA replication. ROS appeared to disrupt active HCV replication complexes, as they reduced the amount of NS3 and NS5A in the subcellular fraction where active HCV RNA replication complexes were found. In conclusion, our results show that ROS can rapidly inhibit HCV RNA replication in human hepatoma cells. The increased ROS levels in hepatitis C patients may therefore play an important role in the suppression of HCV replication.
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PMID:Reactive oxygen species suppress hepatitis C virus RNA replication in human hepatoma cells. 1475 26

Acetaminophen in large doses is well-known as hepatotoxic, and early therapy with N-acetylcysteine is frequently life-saving. However, in later stages of acetaminophen poisoning, treatment with N-acetylcysteine is not always effective. Although some of the pathways of acetaminophen toxicity and the effect of N-acetylcysteine have been elucidated, in depth information on this process is still lacking. Hepatoma-derived HepG2 cultured cells were exposed to acetaminophen (5 and 10 mM), with or without N-acetylcysteine (5 mM), for 24 and 48 hr. For the assessment of oxidative damage, apoptosis and necrosis, we followed redox status, glutathione content, nuclear fragmentation, phosphatidylserine externalization and ultrastructural changes. Variations in Ca2+ level and number of mitochondrial dense granules were also studied. Acetaminophen treatment of HepG2 cells caused oxidative damage and apoptosis. Significant decrease of cellular redox potential and glutathione content were time- and concentration-dependent. The protective effect of N-acetylcysteine was expressed by an increase of intracellular glutathione and of the level of metabolic reduction of the redox indicator Alamar Blue. The apoptogenic effect of acetaminophen was assessed by flow cytometry of annexin V binding, nuclear hypodiploidity, intracellular Ca2+, as well as by ultrastructural examination. Beyond 24 hr of acetaminophen exposure, necrosis was also noticed. We conclude that acetaminophen-induced oxidative damage in HepG2 cultured cells can be prevented by exposure to N-acetylcysteine. However, apoptosis, either early or late, here demonstrated, is not avoided by exposure to N-acetylcysteine. N-Acetylcysteine did not prevent acetaminophen-induced plasma membrane asymmetry, nuclear damage, alterations of Ca2+ homeostasis and ultrastructural changes.
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PMID:N-acetylcysteine does not protect HepG2 cells against acetaminophen-induced apoptosis. 1512 91


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