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)

Green tea polyphenols (GTP) have been demonstrated to suppress tumorigenesis in several chemical-induced animal carcinogenesis models, and predicted as promising chemopreventive agents in human. Recent studies of GTP extracts showed the involvement of mitogen-activated protein kinases (MAPKs) in the regulation of Phase II enzymes gene expression and induction of apoptosis. In the current work we compared the biological actions of five green tea catechins: (1) induction of ARE reporter gene, (2) activation of MAP kinases, (3) cytotoxicity in human hepatoma HepG2-C8 cells, and (4) caspase activation in human cervical squamous carcinoma HeLa cells. For the induction of phase II gene assay, (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) potently induced antioxidant response element (ARE)-mediated luciferase activity, with induction observed at 25 microM with EGCG. The induction of ARE reporter gene appears to be structurally related to the 3-gallate group. Comparing the activation of MAPK by the five polyphenols, only EGCG showed potent activation of all three MAPKs (ERK, JNK and p38) in a dose- and time-dependent manner, whereas EGC activated ERK and p38. In the concentration range of 25 microM to 1 mM, EGCG and ECG strongly suppressed HepG2-ARE-C8 cell-growth. To elucidate the mechanisms of green tea polyphenol-induced apoptosis, we measured the activation of an important cell death protein, caspase-3 induced by EGCG, and found that caspase-3 was activated in a dose- and time-dependent manner. Interestingly, the activation of caspase-3 was a relatively late event (peaked at 16 h), whereas activation of MAPKs was much earlier (peaked at 2 h). It is possible, that at low concentrations of EGCG, activation of MAPK leads to ARE-mediated gene expression including phase II detoxifying enzymes. Whereas at higher concentrations of EGCG, sustained activation of MAPKs such as JNK leads to apoptosis. These mechanisms are currently under investigation in our laboratory. As the most abundant catechin in GTP extract, we found that EGCG potently induced ARE-mediated gene expression, activated MAP kinase pathway, stimulated caspase-3 activity, and induced apoptosis. These mechanisms together with others, may contribute to the overall chemopreventive function of EGCG itself as well as the GTP
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PMID:Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. 1115 83

Chronic hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. The HCV capside core is a multifunctional protein with regulatory functions that affects transcription and cell growth in vitro and in vivo. Here, we show that both HCV genotype 1a and 3 core proteins activate MEK1 and Erk1/2 MAP kinases and that the costitutive expression of the HCV core results in a high basal activity of Raf1 and MAP/kinase/kinase, as determined by endogenous Raf1 in vitro kinase assay and immunodetection of hyperphosphorylated Erk1 and Erk2 even after a serum starvation. Moreover, the activation of both Erk1/2 and the downstream transcription factor Elk-1 in response to the mitogenic stimulus EGF is significantly prolonged. The sustained response to EGF in cells expressing the HCV core occurs despite a normal induction of the MAP phosphatases MKP regulatory feedback and is likely due to the costitutive activation of Raf-1 activity. The ability of HCV core proteins to directly activate the MAP kinase cascade and to prolong its activity in response to mitogenic stimuli may contribute to the neoplastic transformation of HCV infected liver cells.
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PMID:Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. 1142 Jun 71

PR-39, which is an endogenous antimicrobial peptide, can bind to Src homology 3 domains of the NADPH complex protein p47(phox) and the signaling adapter protein p130(Cas). Recently, we have reported that PR-39 gene transduction altered invasive activity and actin structure of human hepatocellular carcinoma cells, suggesting that this peptide affects cellular signaling due to its proline-rich motif. In order to clarify the mechanism of the PR-39 functions, we transfected the PR-39 gene into mouse NIH3T3 cells which had already been transformed with human activated k-ras gene. The PR-39 gene transfectant showed a reorganization of actin structure and suppression of cell proliferation both in vitro and in vivo. Decreases of MAP (mitogen-activated protein) kinase activity, cyclin D1 expression and JNK activity were observed in the PR-39 gene transfectant. Co-immunoprecipitation analysis revealed that PR-39 binds to PI3-kinase p85alpha, which is a regulatory subunit of PI3-kinase and one of the effectors by which ras induces cytoskeletal changes and stimulates mitogenesis. The PI3-kinase activity of the PR-39 gene transfectant was decreased compared with that of the ras transformant. These results suggest that PR-39 alters actin structure and cell proliferation rate by binding to PI3-kinase p85alpha and suppressing the PI3-kinase activity.
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PMID:PI3-kinase p85alpha is a target molecule of proline-rich antimicrobial peptide to suppress proliferation of ras-transformed cells. 1157 64

Previously, we observed that phorbol ester induced more intensive scattering of HepG2 human hepatoma cells than hepatocyte growth factor (HGF). Regulatory components accounting for this intensive migration were studied. Phorbol ester-activated protein kinase C induced the early appearance of a great number of actin stress fibres. Whereas in response to HGF, the activation of phosphatidylinositol 3-kinase initiates the rearrangements of the actin cytoskeleton, in phorbol ester-treated cells, the activation of this enzyme was not required to the actin polymerisation. Activation of Erk1/Erk2 MAP kinases that was essential to the migration had a key role in enhancing the adherence of cells to the extracellular matrix via the increased expression of integrins alpha2, alpha6 and beta1. Protein kinase C stimulated the activation of p21-activated kinase (PAK), as well. However, it also stimulated the selective and transient down-regulation of PAK1, which coincided with the formation of stress fibres.
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PMID:Phorbol ester-induced migration of HepG2 cells is accompanied by intensive stress fibre formation, enhanced integrin expression and transient down-regulation of p21-activated kinase 1. 1253 29

The medicinal mushroom Ganoderma lucidum (G. lucidum) has been used in the Orient for the prevention and treatment of various diseases including cancer. Except for the immune enhancing properties of its polysaccharide constituent, very little is known about the anticancer activity of another major constituent, triterpenes. In this report, we studied the anticancer mechanism of triterpene-enriched extracts from G. lucidum. The triterpene-enriched fraction, WEES-G6, was prepared from mycelia of G. lucidum by sequential hot water extraction, removal of ethanol-insoluble polysaccharides and then gel-filtration chromatography. We found that WEES-G6 inhibited growth of human hepatoma Huh-7 cells, but not Chang liver cells, a normal human liver cell line. Treatment with WEES-G6 caused a rapid decrease in the activity of cell growth regulative protein, PKC, and the activation of JNK and p38 MAP kinases. The changes in these molecules resulted in a prolonged G2 cell cycle phase and strong growth inhibition. None of these effects were seen in the normal liver cells. Our findings suggest that the triterpenes contained in G. lucidum are potential anticancer agents.
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PMID:Triterpene-enriched extracts from Ganoderma lucidum inhibit growth of hepatoma cells via suppressing protein kinase C, activating mitogen-activated protein kinases and G2-phase cell cycle arrest. 1263 3

Although transforming growth factor beta1 (TGF-beta1) acts via the Smad signaling pathway to initiate de novo gene transcription, the TGF-beta1-induced MAPK kinase activation that is involved in the regulation of apoptosis is less well understood. Even though the p38 MAP kinase and c-Jun NH(2)-terminal kinases (JNKs) are involved in TGF-beta1-induced cell death in hepatoma cells, the upstream mediators of these kinases remain to be defined. We show here that the members of the mixed lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper-bearing kinase (DLK)) are expressed in FaO rat hepatoma cells and are likely to act between p38 and TGF-beta receptor kinase in death signaling. TGF-beta1 treatment leads to an increase in MLK3 activity. Overexpression of MLK3 enhances TGF-beta1-induced apoptotic death in FaO cells and Hep3B human hepatoma cells, whereas expression of the dominant-negative forms of MLK3 suppresses cell death induced by TGF-beta1. The dominant-negative forms of MLK1 and -2 also suppress TGF-beta1-induced cell death. In MLK3-overexpressing cells, ERK, JNKs, and p38 MAP kinases were further activated in response to TGF-beta1 compared with the control cells. In contrast, overexpression of the dominant-negative MLK3 resulted in suppression of TGF-beta1-induced MAP kinase activation and TGF-beta1-induced caspase-3 activation. We also show that only the inhibition of the p38 pathway suppressed TGF-beta1-induced apoptosis. These observations support a role for MLKs in the TGF-beta1-induced cell death mechanism.
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PMID:Mixed lineage kinase 3 (MLK3)-activated p38 MAP kinase mediates transforming growth factor-beta-induced apoptosis in hepatoma cells. 1506 87

During the inflammatory response at least 2 transcription factors, NF-kappaB and AP-1, are involved in the altered profile of gene expression. We used human hepatoma (HepG2) and human umbilical vein endothelial cells (HUVEC) as a model system: NF-kappaB and AP-1 were activated by the proinflammatory cytokine IL-1 in the absence or presence of 21 selected plant extracts and the effect was evaluated by the electrophoretic mobility shift assay (EMSA). In both types of cells activation of NF-kappaB by IL-1 was significantly inhibited by extracts from Scandix australis and Artemisia alba, whereas extracts from Amaranthus sp., Eryngium campestre, Thymus pulegioides and Reichardia picroides elicited cell-type dependent response. The IL-1-induced AP-1 activation was diminished by extracts from Scandix australis, Amaranthus sp. and Artemisia alba more potently in HUVEC, while extracts from Urospermum picroides and Scandix pecten-veneris in HepG2 cells. Inhibitory activities of plant extracts towards cytokine activated NF-kappaB and AP-1 depend to some extent on the order of addition of IL-1 and plant extract to the cell culture, but the mechanism of action of extract components is not clear: although plant polyphenols may participate they are unlikely to be the only mediators, and MAP kinases were found generally not involved in down-regulation of transcription factors activity by plant extracts.
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PMID:Transcription factors as targets of the anti-inflammatory treatment. A cell culture study with extracts from some Mediterranean diet plants. 1580 Mar 92

The biological activities of the polysaccharide have attracted more and more attention in the biochemical and medical areas due to their anti-cancer effects. To estimate the anti-tumor mechanism of MAP, a novel polysaccharide from the loach, Misgurnus anguillicaudatus, the apoptosis effects of the polysaccharide on the human hepatocellular carcinoma cells (SMMC-7721 cells) were studied. The present studies showed that MAP could induce cell apoptosis which was closely accompanied with an increase of intracellular-free calcium concentration ([Ca2+]i), the enhancement of reactive oxygen species (ROS) level, dissipation of mitochondria membrane potential (MMP), up-regulation of p53 mRNA, increase expression of Bax mRNA, and decrease expression of Bcl-2 mRNA. These results suggested that cell apoptosis induced by MAP mainly was mediated by mitochondrial pathways, not involved death receptors (DRs) pathways. The mechanism possibly is that MAP acts on mitochondria and boosts ROS, ROS mediates a release of Ca2+ from the intracellular Ca2+ pool, increasing [Ca2+]i targets the cells a start-up of the apoptosis program. However, further research on the molecular mechanisms of MAP effecting on the cells' mitochondria is necessary.
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PMID:Mechanism of apoptosis induced by a polysaccharide, from the loach Misgurnus anguillicaudatus (MAP) in human hepatocellular carcinoma cells. 1593 90

Previous research from our laboratory has shown a switch-like response to PCB 126 mediated CYP1A1 induction in primary rat hepatocytes and in H4IIE rat hepatoma cells. On a single cell level, cells appear to be either "on" or "off" for CYP1A1 induction at a given dose; some cells never respond to PCB 126. These cells represent a non-responding population. Cells that are switched "on" by PCB 126 display varying levels of induction, much like the dimmer on a light switch. The goal of the present research is to begin to uncover the mechanism for this switch-like response to CYP1A1 induction in H4IIE rat hepatoma cells. The AhR pathway is modulated by multiple co-activators and by phosphorylation. This research focuses on the phosphorylation cascades initiated by PCB 126 and the role they play in CYP1A1 induction. Our research reveals a likely role for protein kinase C (PKC) in this switch response. Inhibition of PKC by H-7 dramatically reduced the percent of cells that express CYP1A1 in response to PCB 126 treatment, as determined by flow cytometry. The effect of H-7 was concentration dependent, decreasing the number of cells expressing CYP1A1 rather than decreasing the level of CYP1A1 in all cells. This finding provides further evidence for the switch-like behavior of CYP1A1 induction and implicates PKC in this response to PCB126. The protein kinase inhibitor, HA-1004, had only a minor effect on CYP1A1 induction. A high-throughput immunoblot screen for 40 proteins revealed the regulation of several proteins/phosphoproteins by PCB 126. Most importantly, two proteins containing phosphoserine/phoshothreonine residues were increased by PCB126 treatment. However, PKC translocation studies and activity studies failed to verify that PCB126 activates PKC. It is possible that constitutive PKC activity is sufficient to maintain phosphorylation of critical components of the AhR pathway. Immunoblotting studies showed that MAP kinases ERK and JNK are not activated by PCB 126 in H4IIE cells and the ERK inhibitor U0126 did not impair CYP1A1 induction. Additional studies are planned to further investigate the role of PKC in the switch-like response to PCB 126.
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PMID:Probing the control elements of the CYP1A1 switching module in H4IIE hepatoma cells. 1608 25

Alcohol abuse reduces response rates to IFN therapy in patients with chronic hepatitis C. To model the molecular mechanisms behind this phenotype, we characterized the effects of ethanol on Jak-Stat and MAPK pathways in Huh7 human hepatoma cells, in HCV replicon cell lines, and in primary human hepatocytes. High physiological concentrations of acute ethanol activated the Jak-Stat and p38 MAPK pathways and inhibited HCV replication in several independent replicon cell lines. Moreover, acute ethanol induced Stat1 serine phosphorylation, which was partially mediated by the p38 MAPK pathway. In contrast, when combined with exogenously applied IFN-alpha, ethanol inhibited the antiviral actions of IFN against HCV replication, involving inhibition of IFN-induced Stat1 tyrosine phosphorylation. These effects of alcohol occurred independently of i) alcohol metabolism via ADH and CYP2E1, and ii) cytotoxic or cytostatic effects of ethanol. In this model system, ethanol directly perturbs the Jak-Stat pathway, and HCV replication. Infection with Hepatitis C virus is a significant cause of morbidity and mortality throughout the world. With a propensity to progress to chronic infection, approximately 70% of patients with chronic viremia develop histological evidence of chronic liver diseases including chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The situation is even more dire for patients who abuse ethanol, where the risk of developing end stage liver disease is significantly higher as compared to HCV patients who do not drink 12.Recombinant interferon alpha (IFN-alpha) therapy produces sustained responses (ie clearance of viremia) in 8-12% of patients with chronic hepatitis C 3. Significant improvements in response rates can be achieved with IFN plus ribavirin combination 456 and pegylated IFN plus ribavirin 78 therapies. However, over 50% of chronically infected patients still do not clear viremia. Moreover, HCV-infected patients who abuse alcohol have extremely low response rates to IFN therapy 9, but the mechanisms involved have not been clarified.MAPKs play essential roles in regulation of differentiation, cell growth, and responses to cytokines, chemokines and stress. The core element in MAPK signaling consists of a module of 3 kinases, named MKKK, MKK, and MAPK, which sequentially phosphorylate each other 10. Currently, four MAPK modules have been characterized in mammalian cells: Extracellular Regulated Kinases (ERK1 and 2), Stress activated/c-Jun N terminal kinase (SAPK/JNK), p38 MAP kinases, and ERK5 11. Interestingly, ethanol modulates MAPKs 12. However, information on how ethanol affects MAPKs in the context of innate antiviral pathways such as the Jak-Stat pathway in human cells is extremely limited. When IFN-alpha binds its receptor, two receptor associated tyrosine kinases, Tyk2 and Jak1 become activated by phosphorylation, and phosphorylate Stat1 and Stat2 on conserved tyrosine residues 13. Stat1 and Stat2 combine with the IRF-9 protein to form the transcription factor interferon stimulated gene factor 3 (ISGF-3), which binds to the interferon stimulated response element (ISRE), and induces transcription of IFN-alpha-induced genes (ISG). The ISGs mediate the antiviral effects of IFN. The transcriptional activities of Stats 1, 3, 4, 5a, and 5b are also regulated by serine phosphorylation 14. Phosphorylation of Stat1 on a conserved serine amino acid at position 727 (S727), results in maximal transcriptional activity of the ISGF-3 transcription factor complex 15. Although cross-talk between p38 MAPK and the Jak-Stat pathway is essential for IFN-induced ISRE transcription, p38 does not participate in IFN induction of Stat1 serine phosphorylation 1416171819. However, cellular stress responses induced by stimuli such as ultraviolet light do induce p38 MAPK mediated Stat1 S727 phosphorylation 18. In the current report, we postulated that alcohol and HCV proteins modulate MAPK and Jak-Stat pathways in human liver cells. To begin to address these issues, we characterized the interaction of acute ethanol on Jak-Stat and MAPK pathways in Huh7 cells, HCV replicon cells lines, and primary human hepatocytes.
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PMID:Effect of ethanol on innate antiviral pathways and HCV replication in human liver cells. 1632 17


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