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)

CPT-11, a derivative of camptothecin, induced apoptotic cell death characterized by chromosomal DNA fragmentation in human hepatoma PLC cells in vitro. Cell viability of PLC cells was significantly decreased by CPT-11 in a dose-dependent manner, and CPT-11-induced cytotoxic activity was completely prevented by an interleukin-1 beta converting enzyme-like protease inhibitor YVAD and a protein synthesis inhibitor cycloheximide. To examine the roles of the cytoplasm and the nucleus in CPT-11-induced apoptosis, we prepared cytoplasts from PLC cells and nuclei from rat hepatocytes (RHN). Apoptotic cell death as characterized by cell fragmentation was observed in whole PLC cells but not in PLC cytoplasts after incubation with CPT-11. In addition, CPT-11 could not induce chromosomal DNA fragmentation in RHN. In contrast, the extracts of CPT-11-treated PLC cells, which mainly contained cytosol proteins, induced chromosomal DNA fragmentation of RHN in a dose-dependent manner. These results indicate that CPT-11-induced apoptosis required the presence of both the cytoplasm and the nucleus and suggest that the apoptosis required the de novo synthesis of an apoptosis initiator.
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PMID:Chemotherapeutic agent CPT-11 induces the new expression of the apoptosis initiator to the cytoplasm. 880 62

Various antibacterial compounds, antitumor compounds, enzyme inhibitors and recent signal transduction inhibitors have been discovered from microorganisms and plants. Therefore, it should be possible to find antimetastatic compounds from these sources, if a simple assay system is available. We isolated several enzyme inhibitors from nature to inhibit experimental metastasis. Leupeptin is an old protease inhibitor and inhibited blood-borne lung metastasis of hepatoma cells in rats. A leupeptin analogue inhibiting urokinase inhibited in vitro invasion of human fibrosarcoma cells. Alpha-glucosidase inhibitors such as epi-CPL and baicalein inhibited in vitro invasion and in vivo metastasis of mouse melanoma cells. A mannosidase inhibitor, mannostatin A, also inhibited in vitro invasion of mouse melanoma cells. Oncogene function inhibitors induce normal phenotypes in the oncogene-expressing cells. As expected, they inhibited tumor cell invasion in vitro.
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PMID:Inhibition of experimental metastasis by enzyme inhibitors from microorganisms and plants. 886 51

Transforming growth factor-beta (TGF-beta) is a potent inducer of programmed cell death in liver as well as some hepatoma cell lines. To explore the mechanism by which TGF-beta induces apoptosis, we investigated the role of caspase family proteases in the apoptotic death of a human hepatoma cell line, Hep3B. We showed that TGF-beta-induced apoptosis was blocked by expression of the cowpox virus protein CrmA, a serpin-like pseudosubstrate for some of the caspase family proteases. CrmA expression, however, did not affect TGF-beta-induced regulation of promoter activities of the cyclin A and plasminogen activator inhibitor type I genes. These results indicate that CrmA inhibits a step specific for the apoptotic effect of TGF-beta. In addition to CrmA, a tripeptide caspase-protease inhibitor, z-Val-Ala-Asp-fluoromethylketone could also suppress TGF-beta-induced apoptosis in a dose-dependent manner. In TGF-beta-treated Hep3B cells, we observed a specific degradation of the catalytic subunit of DNA-dependent protein kinase, which was previously shown to be a substrate of caspase-3 but not several other members of the caspase family. This degradation was not seen in Hep3B cells transfected with CrmA nor in Hep3B cells pretreated with the tripeptide caspase inhibitor. Our study indicates a requirement of caspase family proteases in TGF-beta-induced apoptosis.
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PMID:Involvement of caspase family proteases in transforming growth factor-beta-induced apoptosis. 921 76

Our studies have identified a soluble molecule in normal human plasma and serum with the characteristics of the alpha-chain of the low density lipoprotein receptor-related protein (LRP). LRP is a large multifunctional receptor mediating the clearance of diverse ligands, including selected lipoproteins, various protease inhibitor complexes, and thrombospondin. A soluble molecule (sLRP) has been isolated from plasma using an affinity matrix coupled with methylamine-activated alpha2-macroglobulin, the ligand uniquely recognized by LRP, and eluted with EDTA. This eluate contains a protein that co-migrates on SDS-polyacrylamide gel electrophoresis with authentic human placental LRP alpha-chain, is recognized by anti-LRP alpha-chain monoclonal antibodies, and binds the 39-kDa receptor-associated protein (RAP) and tissue plasminogen activator-inhibitor complexes. A similar RAP-binding molecule was detected in medium conditioned for 24 h by primary cultures of rat hepatocytes, suggesting that the liver may be the in vivo source of sLRP. In contrast, immunoprecipitation experiments failed to detect the production of sLRP by cultured HepG2 hepatoma and primary human fibroblast cells. Addition of a soluble form of LRP to cultured HepG2 cells resulted in a significant inhibition of capacity of these cells to degrade tPA, a process that has been demonstrated to be mediated by cell surface LRP. Preliminary data indicate that the concentration of sLRP is altered in the plasma of patients with liver disease. Increased levels of sLRP may antagonize the clearance of ligands by cell bound LRP perturbing diverse processes including lipid metabolism, cell migration and extracellular proteinase activity.
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PMID:Soluble low density lipoprotein receptor-related protein (LRP) circulates in human plasma. 929 45

We have investigated mechanisms of omeprazole (OME)-mediated induction of CYP1A1 and CYP3A, using the rat hepatoma H4IIE cell line, in comparison with mechanisms exerted by traditional aryl hydrocarbon receptor (AhR) ligands such as benso(a)pyrene (B(a)P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). OME did not bind specifically to AhR, and it could not activate the AhR complex in rat cytosol to a xenobiotic-responsive element (XRE)-binding form in vitro. Genistein, a tyrosine kinase inhibitor, and daidzein, an inhibitor of casein kinase II, efficiently inhibited OME-mediated but not B(a)P- or TCDD-mediated induction of CYP1A1, as monitored at the transcriptional, mRNA, and protein levels as well as by analysis of activation of XRE-luciferase reporter constructs transfected into H4IIE cells. The protease inhibitor Nalpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) and lavendustin A also had similar OME-specific effects. In addition, insulin pretreatment caused an almost complete inhibition of OME-dependent CYP1A1 induction but only partially affected TCDD and B(a)P-mediated induction of CYP1A1. Staurosporine, an inhibitor of protein kinase C, impaired the induction by both B(a)P and OME. OME caused an approximately 2-fold increase in the level of CYP3A expression, but all inhibitors used were ineffective in preventing this induction. Gel shift analysis with radiolabeled XRE and specific peptide antibodies toward AhR and aryl hydrocarbon receptor nuclear translocator protein (Arnt) revealed an OME-mediated translocation of the AhR.Arnt complex into the nuclei. Genistein inhibited the specific nuclear XRE binding caused by OME, but it potentiated the formation of the TCDD-induced XRE.AhR complex. Although daidzein was able to effectively inhibit the OME-stimulated CYP1A1 gene transcription, it did not influence the OME-dependent AhR.XRE complex formation. The data are consistent with a mechanism for OME-mediated induction of CYP1A1 that involves activation of the AhR complex via intracellular signal transduction systems and that is distinct from induction mediated by AhR ligands.
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PMID:Signal transduction-mediated activation of the aryl hydrocarbon receptor in rat hepatoma H4IIE cells. 939 20

The multiligand receptor, low density lipoprotein receptor-related protein (LRP), is implicated in processes such as atherosclerosis and fibrinolysis through its mediation of the catabolism of lipoproteins, proteases, and protease inhibitor complexes. The hepatoma cell line Hep G2 expresses LRP and has been used widely to investigate the catabolism of LRP ligands including tissue-type plasminogen activator (tPA). However, the mechanism and degree by which tPA interacts with Hep G2 has been reported with some inconsistencies which may reflect variation in their level of LRP expression. To address this possibility we characterized, antigenically and functionally, LRP expression in high and low passage Hep G2 cells both from the parental line (ATCC sourced) and a cloned subline, a16. The LRP contribution to 125I-tPA binding varied from 65% for high passage a16 cells, to 20% for low passage parent cells as quantified by inhibition in the presence of 39-kD receptor associated protein (RAP) which prevents binding of all known LRP ligands. The same trend in LRP expression among Hep G2 sublines was further evident in their ability to degrade 125I-tPA and survive Pseudomonas exotoxin A challenge. These results imply wide variability in basal LRP expression among Hep G2 lines dependent on cell lineage and long-term culture conditions.
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PMID:Low density lipoprotein receptor-related protein (LRP) expression varies among Hep G2 cell lines. 961 Sep 60

A 67-year-old male patient with pulmonary emphysema was diagnosed with liver cirrhosis. Further investigations revealed an alpha 1-antitrypsin deficiency caused by a PiZZ mutation. The liver cirrhosis was complicated by the development of a hepatocellular carcinoma. The patient died from the consequences of mesentary vein thrombosis. The protease inhibitor alpha 1-antitrypsin controls the tissue damaging effects of proteases which are produced by granulocytes. In the case of alpha 1-antitrypsin deficiency, progressive damage of the lung tissue occurs, resulting in emphysema. The accumulation of abnormal alpha 1-antitrypsin in hepatocytes can result in cirrhosis, with an increased chance of carcinoma. The deficiency is caused by a mutation in the Pi-gene on chromosome number 14. Although treatment options are at present limited, making an early diagnosis has important implications for the prognosis and intended management with respect to the prevention of complications, both in the patient as well as in first degree relatives (children and siblings).
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PMID:[Primary liver cell carcinoma as complication of alpha 1-antitrypsin deficiency in a 67 year old man]. 1110 73

The classical form of alpha 1-antitrypsin (alpha 1-AT) deficiency is associated with a mutant alpha 1-ATZ molecule that polymerizes in the endoplasmic reticulum (ER) of liver cells. A subgroup of individuals homozygous for the protease inhibitor (PI) Z allele develop chronic liver injury and are predisposed to hepatocellular carcinoma. In this study we evaluated the primary structure of alpha 1-AT in a family in which three affected members had severe liver disease associated with alpha 1-AT deficiency. We discovered that one sibling was a compound heterozygote with one PI Z allele and a second allele, the PI Z + saar allele, bearing the mutation that characterizes alpha 1-ATZ as well as the mutation that characterizes alpha 1-AT Saarbrucken (alpha 1-AT saar). The mutation in PI saar introduces a premature termination codon resulting in an alpha 1-AT protein truncated for 19 amino acids at its carboxyl terminus. Studies of a second sib with severe liver disease and other living family members did not reveal the presence of the alpha 1-AT saar mutation and therefore do not substantiate a role for this mutation in the liver disease phenotype of this family. However, studies of alpha 1-AT saar and alpha 1-ATZ + saar expressed in heterologous cells show that there is prolonged intracellular retention of these mutants even though they do not have polymerogenic properties. These results therefore have important implications for further understanding the fate of mutant alpha 1-AT molecules, the mechanism of ER retention, and the pathogenesis of liver injury in alpha 1-AT deficiency.
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PMID:A naturally occurring nonpolymerogenic mutant of alpha 1-antitrypsin characterized by prolonged retention in the endoplasmic reticulum. 1142 40

Highly active anti-retroviral therapies, which incorporate HIV protease inhibitors, resolve many AIDS-defining illnesses. However, patients receiving protease inhibitors develop a marked lipodystrophy and hyperlipidemia. Using cultured human and rat hepatoma cells and primary hepatocytes from transgenic mice, we demonstrate that protease inhibitor treatment inhibits proteasomal degradation of nascent apolipoprotein B, the principal protein component of triglyceride and cholesterol-rich plasma lipoproteins. Unexpectedly, protease inhibitors also inhibited the secretion of apolipoprotein B. This was associated with inhibition of cholesteryl-ester synthesis and microsomal triglyceride transfer-protein activity. However, in the presence of oleic acid, which stimulates neutral-lipid biosynthesis, protease-inhibitor treatment increased secretion of apolipoprotein B-lipoproteins above controls. These findings suggest a molecular basis for protease-inhibitor-associated hyperlipidemia, a serious adverse effect of an otherwise efficacious treatment for HIV infection.
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PMID:HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. 1192 15

Hepatitis C Virus (HCV) NS3 protease is an attractive target for antiviral agent development because it is required for viral replication. Because a stable cell culture system or small animal model to study HCV replication is not readily available, we constructed an in vitro model allowing the investigation of NS3 transcription, translation, and protease function. Sequences encoding for full length HCV genomes were cloned and transfected into HuH-7 human hepatocellular carcinoma cells to analyze NS3 transcription/translation. A plasmid pHCV ORF I luc that expresses the complete HCV coding region upstream of a luciferase reporter gene was designed to enable quantification of translated HCV proteins. Additionally, NS3 protease function was assessed by direct coexpression of NS3 and NS5 in HuH 7 cells, and the subsequent measurement of cleavage products. We found that antisense oligodeoxynucleotides (AS-ODN) interfered with NS3 translation in a dose dependent fashion; AS-ODN 5 cotransfection directed against NS3 sequences significantly inhibited protease activity as measured by cleaved NS5A levels. Finally, cleaved NS5A levels served as anindex of protease activity and Chymostatin, a protease inhibitor, almost completely blocked NS3 enzymatic activity. This cell culture system is useful in the assessment of potential antiviral agents on HCV NS3 expression and function.
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PMID:Inhibition of hepatitis C virus NS3 function by antisense oligodeoxynucleotides and protease inhibitor. 1174 30


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