Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The TNF-receptor family has a dual signaling pathway, including induction of apoptosis and NF-kappaB activation associated with cell survival. Hepatocellular carcinoma (HCC) cells express TNF-receptor family members and the signaling from these receptors induces NF-kappaB activation. However, the role of Fas in induction of NF-kappaB activation in HCC cells is not well understood. In this study, SK-Hep1, HepG2 or HLE cells were stimulated by anti-Fas agonistic antibody. Fas stimulation induced NF-kappaB activation in a dose-dependent manner in SK-Hep1 and HepG2 cell lines, but not in HLE cells. Anti-Fas agonistic antibody or the metabolic inhibitor, cyclo-heximide (CHX), failed to kill SK-Hep1 cells, but co-incubation with anti-Fas agonistic antibody and CHX was effective for induction of apoptosis. SK-Hep1 cell lines receiving Fas stimulation had increased viability, but the extent of cell proliferation was not dose-dependent. The observation suggests that Fas stimulation may contribute to HCC cell survival or proliferation.
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PMID:Fas stimulation activates NF-kappaB in SK-Hep1 hepatocellular carcinoma cells. 1288 71

Two genes (MAT1A and MAT2A) encode for methionine adenosyltransferase (MAT), an essential cellular enzyme responsible for S-adenosylmethionine biosynthesis. MAT1A is expressed mostly in the liver, whereas MAT2A is widely distributed. We showed a switch from MAT1A to MAT2A expression in human hepatocellular carcinoma (HCC), which facilitates cancer cell growth. Using DNase I footprinting analysis, we previously identified a region in the MAT2A promoter protected from DNase I digestion in HCC. This region contains NF-kappa B and AP-1 elements, and the present study examined whether they regulate MAT2A promoter activity. We found nuclear binding of NF-kappa B and AP-1 to the MAT2A promoter increased in HCC. Tumor necrosis factor alpha (TNFalpha), which activates both NF-kappa B and AP-1, increased MAT2A expression in a dose- and time-dependent manner, binding of both NF-kappa B and AP-1 to the MAT2A promoter and MAT2A promoter activity, with the latter effect blocked by site-directed mutagenesis of the NF-kappa B and AP-1 binding sites. Blocking NF-kappa B with I kappa B super-repressor or AP-1 with dominant-negative c-Jun led to decreased basal MAT2A expression and prevented the TNF alpha-induced increase in MAT2A expression. Although blocking NF-kappa B had no influence on the ability of TNF alpha to increase AP-1 nuclear binding, blocking AP-1 with dominant-negative c-Jun prevented the TNF alpha-mediated increase in NF-kappa B binding. In conclusion, both NF-kappa B and AP-1 are required for basal MAT2A expression in HepG2 cells and mediate the increase in MAT2A expression in response to TNF alpha treatment. Increased trans-activation of these two sites also contributes to MAT2A up-regulation in HCC.
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PMID:Induction of human methionine adenosyltransferase 2A expression by tumor necrosis factor alpha. Role of NF-kappa B and AP-1. 1453 Feb 85

The peroxisome proliferator-activated receptor-gamma (PPARgamma) high-affinity ligand, 15-deoxy-Delta-12,14-PGJ(2) (15d-PGJ(2)), is toxic to malignant cells through cell cycle arrest and apoptosis induction. In this study, we investigated the effects of 15d-PGJ(2) on apoptosis induction and expression of apoptosis-related proteins in hepatocellular carcinoma (HCC) cells. 15d-PGJ(2) induced apoptosis in SK-Hep1 and HepG2 cells at a 50 micro M concentration. Pretreatment with the pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (2-VAD-fmk), only partially blocked apoptosis induced by 40 micro M 15d-PGJ(2). This indicated that 15d-PGJ(2) induction of apoptosis was associated with a caspase-3-independent pathway. 15d-PGJ(2) also induced down-regulation of the X chromosome-linked inhibitor of apoptosis (XIAP), Bclx, and apoptotic protease-activating factor-1 in SK-Hep1 cells but not in HepG2 cells. However, 15d-PGJ(2) sensitized both HCC cell lines to TNF-related apoptosis-induced ligand-induced apoptosis. In SK-Hep1 cells, cell toxicity, nuclear factor-kappaB (NF-kappaB) suppression, and XIAP down-regulation were induced by 15d-PGJ(2) treatment under conditions in which PPARgamma was down-regulated. These results suggest that the effect of 15d-PGJ(2) was through a PPARgamma-independent mechanism. Although cell toxicity was induced when PPARgamma was down-regulated in HepG2 cells, NF-kappaB suppression and XIAP down-regulation were not induced. In conclusion, 15d-PGJ(2) induces apoptosis of HCC cell lines via caspase-dependent and -independent pathways. In SK-Hep1 cells, the ability of 15d-PGJ(2) to induce cell toxicity, NF-kappaB suppression, or XIAP down-regulation seemed to occur via a PPARgamma-independent mechanism, but in HepG2 cells, NF-kappaB suppression by 15d-PGJ(2) was dependent on PPARgamma.
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PMID:15-deoxy-delta-12-14-PGJ2 regulates apoptosis induction and nuclear factor-kappaB activation via a peroxisome proliferator-activated receptor-gamma-independent mechanism in hepatocellular carcinoma. 1456 54

Plasma inflammatory cytokines are elevated in obese subjects as well as in those with type 2 diabetes. This presumably results in systemic insulin resistance, characterized by a pro-atherogenic plasma lipid profile and reduced apolipoprotein AI (apoAI) protein levels. To determine how cytokine-mediated insulin resistance suppresses apoAI gene expression, we investigated the effect of tumor necrosis factor alpha (TNF alpha) and interleukin-1beta (IL-1beta) on apoAI protein, mRNA, and transcriptional activity in the human hepatoma cell line HepG2. ApoAI secretion was suppressed in a dose-dependent manner in HepG2 cells treated with both cytokines. ApoAI protein levels were 2892+/-22.0, 2263+/-117, 2458+/-25.0, 3401+/-152, 2333+/-248, 1520+/-41.5 and 956.0+/-11.0 arbitrary units (AU) in cells treated with 0, 0.3, 1.0, 3.0, 10, 30, and 100 ng/ml TNF alpha, achieving statistical significance in the 30 and 100 ng/ml range (P<0.0009). ApoAI protein levels were 4055+/-360, 3697+/-101, 3347+/-327, 1561+/-33.0, 1581+/-182, 810.0+/-59.5, and 1766+/-717 AU in cells treated with similar doses of IL-1beta, achieving statistical significance within the range of 3-100 ng/ml (P<0.02). ApoAI mRNA levels were suppressed 50.8% in HepG2 cells treated with 30 ng/ml TNF alpha for 24 h (P<0.05), and remained suppressed for up to 96 h. Similarly, treatment of cells with 30 ng/ml IL-1beta for 24 h, resulted in 42.9% reduction in apoAI mRNA levels (P<0.05) and remained suppressed for up to 96 h. In order to determine if the effect of TNF alpha and IL-1beta occurs at the transcriptional level, HepG2 cells were transfected with a chloramphenicol acetyltransferase (CAT) reporter gene plasmid containing the full-length apoAI promoter, and after 24 h, treated with TNF alpha (30 ng/ml), IL-1beta (30 ng/ml), or both cytokines. CAT activity was suppressed by both cytokines (24.0+/-1.9% acetylation in control cells vs. 5.6+/-1.2% (P<0.0004), 10.2+/-1.5% (P<0.0006), and 3.9+/-0.9% acetylation (P<0.0002) in cells treated with TNF alpha, IL-1beta, and the combination of both cytokines, respectively) suggesting that cytokine-mediated suppression occurs at the transcriptional level. Using a series of apoAI deletion constructs, the cytokine response element was mapped between nucleotides -325 and -186 (relative to the transcriptional start site). This region contains a previously identified and characterized cis-element, site A, which binds several different transcription factors. Finally, electrophoretic mobility shift assays (EMSA) showed that TNF alpha treatment of HepG2 cells is associated with reduced nuclear factor binding to site A. These studies suggest that inflammatory cytokines down-regulate apoAI expression at least partly through inhibition of binding of the nuclear factors to site A of the apoAI promoter.
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PMID:Suppression of apolipoprotein AI gene expression in HepG2 cells by TNF alpha and IL-1beta. 1457 9

Mitochondrion is one of the master players in both apoptosis and necrosis. However, most previous articles report that mitochondrial DNA-depleted cells without oxidative phosphorylation underwent apoptosis by several apoptotic effectors as efficiently as their parental cells, suggesting that intact mitochondrial function is dispensable for the progression of apoptosis. We studied the role of mitochondrial function in several apoptosis models. TRAIL, a recently identified member of the TNF family with cytotoxicity on a wide variety of transformed cells, killed SK-Hep1 cells with characteristic features of apoptosis such as DNA fragmentation, sub-G1 ploidy peak, and cytochrome c translocation. In contrast with parental cells, mitochondrial DNA-deficient SK-Hep1 rho(0) cells were resistant to TRAIL-induced apoptosis. Dissipation of mitochondrial potential or cytochrome c translocation did not occur in rho(0) cells after TRAIL treatment. Bax translocation also was absent in rho(0) cells, accounting for the failure of cytochrome c release in rho(0) cells. SK-Hep1 rho(0) cells were resistant to other death effectors such as staurosporine. Our results indicate that apoptosis of SK-Hep1 hepatoma cells is dependent on intact mitochondrial function. Because aged cells or tumor cells have frequent mutations or deletions of mitochondrial DNA, they might acquire the ability to evade apoptosis or tumor surveillance imposed by TRAIL or other death effectors in vivo, accounting for the selection advantage of cancer cells and frequent development of cancer in aged individuals.
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PMID:Resistance of rho(0) cells against apoptosis. 1512 92

TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF family whose transcripts are expressed in various human tissues. Since TWEAK has a variety of biological activities, we investigated TWEAK sensitivity, expression, and physiological role in human hepatocellular carcinomas (HCCs). Tweak receptor was detected in four kinds of HCC cells. TWEAK significantly promoted cell proliferation and induced nuclear factor-kappaB activation in all HCC cells. Surprisingly, we found that HCC cells constitutively express TWEAK. In addition, soluble TWEAK was detected in culture medium. We found that TWEAK also promotes cell proliferation and induces the secretion of IL-8 and MCP-1 in human umbilical vein endothelial cell. Finally, culture medium from Sh-Hep1 cells incubated with anti-TWEAK antibody significantly inhibited endothelial cell tube formation. In conclusion, these results indicate that TWEAK might play a critical role in HCC cellular proliferation using both autocrine and paracrine mechanisms, and modulate tumor-related angiogenesis.
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PMID:Functional expression of TWEAK in human hepatocellular carcinoma: possible implication in cell proliferation and tumor angiogenesis. 1514 99

The key insulin-regulated gluconeogenic enzyme G6Pase (glucose-6-phosphatase) has an important function in the control of hepatic glucose production. Here we examined the inhibition of G6Pase gene transcription by TNF (tumour necrosis factor) in H4IIE hepatoma cells. TNF decreased dexamethasone/dibtuyryl cAMP-induced G6Pase mRNA levels. TNFalpha, but not insulin, led to rapid activation of NFkappaB (nuclear factor kappaB). The adenoviral overexpression of a dominant negative mutant of IkappaBalpha (inhibitor of NFkappaB alpha) prevented the suppression of G6Pase expression by TNFalpha, but did not affect that by insulin. The regulation of G6Pase by TNF was not mediated by activation of the phosphoinositide 3-kinase/protein kinase B pathway, extracellular-signal-regulated protein kinase or p38 mitogen-activated protein kinase. Reporter gene assays demonstrated a concentration-dependent down-regulation of G6Pase promoter activity by the transient overexpression of NFkappaB. Although two binding sites for NFkappaB were identified within the G6Pase promoter, neither of these sites, nor the insulin response unit or binding sites for Sp proteins, was necessary for the regulation of G6Pase promoter activity by TNFalpha. In conclusion, the data indicate that the activation of NFkappaB is sufficient to suppress G6Pase gene expression, and is required for the regulation by TNFalpha, but not by insulin. We propose that NFkappaB does not act by binding directly to the G6Pase promoter.
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PMID:Tumour necrosis factor alpha decreases glucose-6-phosphatase gene expression by activation of nuclear factor kappaB. 1516 11

The acute-phase response (APR) induces alterations in lipid metabolism, and our data suggest that this is associated with suppression of type II nuclear hormone receptors that are key regulators of fatty acid, cholesterol, and bile acid metabolism. Recently, the farnesoid X receptor (FXR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR) were found to regulate DHEA sulfotransferase (Sult2A1), which plays an important role in DHEA sulfation and detoxification of bile acids. Because FXR, PXR, and CAR are suppressed during the APR, we hypothesized that Sult2A1 is downregulated during the APR. To induce the APR, mice were treated with LPS, which will then trigger the release of various cytokines, and the mRNA levels of Sult2A1 and the sulfate donor 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2), as well as the enzyme activity of Sult2A1, were determined in the liver. We found that mRNA levels of Sult2A1 decrease in a time- and dose-dependent manner during the LPS-induced APR. Similar changes were observed in the mRNA levels of PAPSS2, the major synthase of PAPS in the liver. Moreover, hepatic Sult2A1 activity and serum levels of DHEA-sulfate (DHEA-S) were significantly decreased in LPS-treated animals. These results suggest that decreased levels or activities of FXR, PXR, and CAR during the APR could contribute to decreases in Sult2A1, resulting in decreased sulfation of DHEA and lower circulating level of DHEA-S. Finally, we found that both TNF and IL-1 caused a significant decrease in the mRNA level of Sult2A1 in Hep3B human hepatoma cells, suggesting that the proinflammatory cytokines TNF and IL-1 mediate the inhibitory effect of LPS on Sult2A1 mRNA level. Our study provides a possible mechanism by which infection and inflammation are associated with altered steroid metabolism and cholestasis.
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PMID:Suppression of DHEA sulfotransferase (Sult2A1) during the acute-phase response. 1519 32

Apoptosis is known to play a critical role in development and homeostasis in metazoans. Although apoptotic responses vary widely among cell types, the underlying mechanisms responsible for these differences are not known. In order to understand the molecular basis for these differences, we have studied a cell culture model comparing hepatoma cells to dedifferentiated cell lines derived from them. We recently reported evidence suggesting that a common regulatory locus affects both liver-specific function and sensitivity to lipopolysaccharide (LPS)-mediated apoptosis. Here, we show that dedifferentiated hepatoma cells undergo apoptosis in response to multiple compounds, including sorbitol (to induce hyperosmotic shock), TNF alpha and the microtubule damaging agent vinblastin. In contrast, the hepatoma parental cells fail to undergo apoptosis in response to any of the compounds tested. Further analysis of LPS-mediated cell death found that antioxidants N-acetylcysteine and alpha-tocopherol partially prevented apoptosis. Lastly, evidence is presented showing that LPS-mediated cell death of the hepatoma variant cell lines is caspase-dependent. These results suggest that pathways dictating hepatic phenotype also affect general cellular survival mechanisms in response to multiple agents. The dedifferentiated cells provide a model to examine the influence of cell-type specific expression on apoptotic signaling.
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PMID:Tissue-specificity of apoptosis in hepatoma-derived cell lines. 1525 69

Glutathione (GSH) is important in free radical scavenging, maintaining cellular redox status, and regulating cell survival in response to a wide variety of toxicants. The rate-limiting enzyme in GSH synthesis is glutamate-cysteine ligase (GCL), which is composed of catalytic (GCLC) and modifier (GCLM) subunits. To determine whether increased GSH biosynthetic capacity enhances cellular resistance to tumor necrosis factor-alpha- (TNF-alpha-) induced apoptotic cell death, we have established several mouse liver hepatoma (Hepa-1) cell lines overexpressing GCLC and/or GCLM. Cells overexpressing GCLC alone exhibit modest increases in GCL activity, while cells overexpressing both subunits have large increases in GCL activity. Importantly, cells overexpressing both GCL subunits exhibit increased resistance to TNF-induced apoptosis as judged by a loss of redox potential; mitochondrial membrane potential; translocation of cytochrome c to the cytoplasm; and activation of caspase-3, caspase-8, and caspase-9. Analysis of the effects of TNF on these parameters indicates that maintaining mitochondrial integrity mediates this protective effect in GCL-overexpressing cells.
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PMID:Glutamate-cysteine ligase attenuates TNF-induced mitochondrial injury and apoptosis. 1528 21


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