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)

Gankyrin is an oncoprotein overexpressed in hepatocarcinoma cells that binds to the cell-cycle regulator CDK4 and the S6b ATPase subunit of the regulatory component of the proteasome. It belongs to the family of ankyrin-repeat proteins that appear to mediate protein-protein interactions in diverse biochemical processes. Gankyrin has been crystallized from polyethylene glycol solutions and diffraction data have been obtained from these crystals that extend to 2.1 A spacing.
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PMID:Crystallization of gankyrin, an oncoprotein that interacts with CDK4 and the S6b (rpt3) ATPase of the 19S regulator of the 26S proteasome. 1283 91

The ubiquitin-proteasome system is involved in a variety of biological processes. Inclusion bodies associated with intermediate filaments (IFs) and ubiquitin are observed in various diseases; however, the precise mechanisms of formation and the pathological significance of inclusion bodies have not been fully understood. We examined the effect of proteasome inhibitors on the structure of IF using anti-cytokeratin antibodies or transfection of green fluorescent protein-fused cytokeratin 18 in a hepatoma cell line, Huh7. Intracellular organelles were visualized by immunofluorescent and electron microscopies. Proteasome inhibitors induced IF inclusions associated with ubiquitin. Electron microscopic examination revealed inclusion bodies surrounded by filamentous structures. Autophagic vacuoles and lysosomes were frequently observed, and the organization of the Golgi apparatus was disrupted in these cells. After the removal of the proteasome inhibitors, the IF network and organization of the Golgi apparatus were restored. The IF inclusions could be induced by inhibition of the proteasome function. IF inclusions induced fragmentation of the Golgi apparatus and might inhibit the function of this important station of membrane traffic. The IF inclusions disappeared by restoring proteasome function, and autophagy and lysosomal degradation might be, at least in part, associated with the elimination of inclusion bodies.
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PMID:Proteasome inhibition induces inclusion bodies associated with intermediate filaments and fragmentation of the Golgi apparatus. 1287 59

TCDD (2,3,7,8-tetrachlorodibenzo- p -dixoin) induces phase II drug-metabolizing enzyme NQO1 [NAD(P)H:quinone oxidoreductase; EC 1.6.99.2; DT-diaphorase] in a wide range of mammalian tissues and cells. Here, we analysed the molecular pathway mediating NQO1 induction by TCDD in mouse hepatoma cells. Inhibition of protein synthesis with CHX (cycloheximide) completely blocks induction of NQO1 by TCDD as well as the basal expression and induction by phenolic antioxidant tBHQ (2-t-butylbenzene-1,4-diol), implicating a labile factor in NQO1 mRNA expression. The inhibition is both time- and concentration-dependent, requires inhibition of protein synthesis, and occurs at a transcriptional level. Inhibition of NQO1 transcription by CHX correlates with a rapid reduction of the CNC bZip (cap 'n' collar basic leucine zipper) transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) through the 26 S proteasome pathway. Moreover, blocking Nrf2 degradation with proteasome inhibitor MG132 increases the amount of Nrf2 and superinduces NQO1 in the presence of TCDD or tBHQ. Finally, genetic experiments using AhR (aryl hydrocarbon receptor)-, Arnt (aryl hydrocarbon receptor nuclear translocator)- or Nrf2-deficient cells reveal that, while induction of NQO1 by TCDD depends on the presence of AhR and Arnt, the basal and inducible expression of NQO1 by either TCDD or tBHQ requires functional Nrf2. The findings demonstrate a novel role of Nrf2 in the induction of NQO1 by TCDD and provide new insights into the mechanism by which Nrf2 regulates the induction of phase II enzymes by both phenolic antioxidants and AhR ligands.
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PMID:Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap 'n' collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2): cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction. 1451 Jun 36

Breakdown of cellular proteins is a highly regulated process, and the ubiquitin-proteasome pathway is the major proteolytic system in the cell. It regulates the levels of numerous proteins that control gene expression and cell division, as well as responses to stress and inflammation. Recent studies have reported abnormalities in proteasome function in alcoholic liver disease (ALD). Moreover, a direct relation has been reported between impaired proteasome function and oxidative stress in experimental models of ALD. Neutrophil infiltration is a hallmark of ALD, and activated neutrophils are thought to play a role in the pathology of ALD. As a potent neutrophil chemoattractant and activator, interleukin 8 (IL-8) likely plays a key mechanistic role in many forms of liver injury. In this study, we evaluated the effects of inhibition of proteasome function on expression and release of IL-8 by human fetal hepatocytes and hepatoma cells. Our data demonstrate that inhibition of proteasome function in hepatocytes leads to apoptotic cell death. Decreased hepatocyte survival coincides with enhanced expression of IL-8, both at the protein and the messenger RNA (mRNA) levels. This increase in IL-8 is independent of nuclear factor kappaB (NF-kappaB) activation and is associated with an increase in c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) activity. In conclusion, hepatocytes dying because of inhibition of proteasome function produce massive quantities of the proinflammatory chemokine IL-8, possibly resulting in neutrophil infiltration, increased inflammation, and liver injury.
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PMID:Inhibition of proteasome function leads to NF-kappaB-independent IL-8 expression in human hepatocytes. 1457 56

Growth factor deprivation-induced apoptosis has been shown in various cell systems and is recognized as one of the standard models for the study of programmed cell death. The mechanism of induction of apoptosis by serum deprivation is still not clear. The objective of the present study was to investigate if serum-deprivation causes oxidative stress, which then leads to apoptotic death. We have demonstrated that indeed, there was a significant increase in reactive oxygen species following serum deprivation of 5123tc hepatoma cells. Furthermore, treatment with anti-oxidants; melatonin or vitamin E, prevented cell death caused by serum-deprivation. We also demonstrated that there was activation of proteasome proteases and decrease in glutathione levels following serum deprivation. Interestingly, melatonin treatment blocked these changes and rescued the cells from apoptosis induced by serum-deprivation. These results indicated that oxidative stress may play a causal role in the induction of apoptosis induced by serum deprivation.
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PMID:Oxidative stress and activation of proteasome protease during serum deprivation-induced apoptosis in rat hepatoma cells; inhibition of cell death by melatonin. 1460 56

In our study, we examined whether human hepatocellular carcinoma (HCC) expresses peroxisome proliferator-activated receptor gamma (PPARgamma) and the effects of PPAR gamma activation by its selective ligands on cell growth and cell invasion in HCC cells. RT-PCR and Western blot analysis revealed that HCC-derived cell lines, HepG2 and HLF, express PPARgamma mRNA and protein. Luciferase assay in HLF cells showed that troglitazone, a selective ligand for PPAR gamma, transactivated the transcription of a peroxisome proliferator response element-driven promoter in a dose-dependent manner, suggesting that the expressed PPARgamma functions as a transcriptional factor. Not only troglitazone but pioglitazone dose-dependently inhibited cell growth in HepG2 and HLF cells. Invasion assay using a transwell chamber demonstrated that troglitazone also inhibited cell invasion in HCC cells. To examine the mechanism of the troglitazone-induced growth inhibition, we determined p27(Kip1), a cyclin dependent kinase inhibitor, expression by Western blot analysis in troglitazone-treated HLF cells. Troglitazone increased p27(Kip1) in time- and dose-dependent manners, suggesting that p27(Kip1) may be involved in the growth inhibition by troglitazone in HLF cells. To further examine the mechanism of the troglitazone-induced p27(Kip1) protein accumulation, 2 major systems for regulation of p27(Kip1) protein, proteasome activity and Skp2, an F-box protein that targets p27(Kip1) for degradation, were evaluated. Troglitazone potently inhibited proteasome activity and decreased Skp2 protein levels. All these results suggest that human HCC cells express functional PPAR gamma and PPARgamma activation resulted in growth inhibition. The growth inhibition was mediated by p27(Kip1) accumulation, which is induced by both inhibition of ubiquitylation of p27(Kip1) and reduction of degradation activity of p27Kip1 by proteasome.
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PMID:Growth arrest by troglitazone is mediated by p27Kip1 accumulation, which results from dual inhibition of proteasome activity and Skp2 expression in human hepatocellular carcinoma cells. 1461 13

Mallory body (MB) experimental induction takes 10 weeks of drug ingestion. Therefore, it is difficult to study the dynamics and mechanisms involved in vivo. Consequently, an in vitro study was done using primary tissue culture of hepatocytes from drug-primed mice livers in which MBs had already formed. The hypothesis to be tested was that MBs are cytokeratin aggresomes, which form when hepatocytes have a defective ubiquitin-proteasome pathway by which turnover of cytokeratin proteins is prevented. To test this hypothesis, primary tissue cultures of the hepatocytes from normal and MB-forming livers were incubated with the proteasome inhibitor PS-341 and then the cytokeratin filaments and the filament connecting proteins, that is, beta-actin, and ZO1, were visualized by immunofluorescence microscopy. PS-341 caused detachment of the cytokeratins from the cell surface plasma membrane. The cytokeratin filaments retracted toward the nucleus and cytokeratin aggresomes formed. In human livers, MBs showed colocalization of cytokeratin-8 (CK-8) with ubiquitin but not with beta-actin or ZO1. Mouse hepatoma cell lines were studied using PS-341 to induce cytokeratin aggresome formation. In these cell lines, the cytokeratin filaments first retracted toward the nucleus then formed cytokeratin-ubiquitin aggresomes polarized at one side of the nucleus. At the same time, the cells became dissociated from each other, however. The results simulated MB formation. MBs differ from cytokeratin aggresomes both morphologically and in ultrastructure.
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PMID:The proteasome inhibitor, PS-341, causes cytokeratin aggresome formation. 1473 63

We here review therapeutic application of a synthetic analog of retinoids (vitamin A and its derivatives), named acyclic retinoid (AR), towards chemoprevention of hepatocellular carcinoma (HCC), and its underlying molecular mechanisms. A high incidence of post-therapeutic recurrence has become a major determinant of the prognosis of HCC, especially in the patients of hepatitis virus-infected cirrhosis. Oral supplementation of AR successfully prevented the recurrence of HCC, associated with a disappearance in serum levels of lectin-reactive alpha-fetoprotein (AFP-L3), a marker of occult cancer clones in the liver, suggesting eradication of latent malignant clones from patients' liver. This led us a novel concept of 'clonal deletion' with AR as an agent that is conceptually similar to cancer chemotherapy. HCC in cirrhotic patients contains lower levels of endogenous retinoids and simultaneously is insensitive to retinoic acid (RA) because of malfunction of its nuclear receptor, retinoid X receptor alpha (RXRalpha). In HCC tissues, RXRalpha is constitutively phosphorylated by the action of extracellular signal-regulated kinase (Erk), thereby losing its transactivation activity and becoming resistant to degradation via ubiquitin/proteasome pathway. This leads to accumulation of phospho-inactivated RXRalpha, that functions as a dominant negative receptor and interferes with transactivation by remaining normal RXRalpha. AR but not natural RA prevents phosphorylation of RXRalpha and restores the function of RXRalpha via down-regulating Ras/Erk system, making HCC cells sensitive to the endogenous ligand, 9-cis-RA. This may link to both caspase-dependent and -independent apoptosis of the cancer cells via induction of growth suppressor(s) such as p21CIP1 and/or apoptosis inducer(s) including tissue transglutaminase. AR also enhances the sensitivity of HCC cells to interferons-alpha and -beta, and thereby indirectly promotes apoptosis induced by these interferons. In summary, our clinical experience and basic research together provide a strong rationale to use AR in the chemoprevention of HCC.
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PMID:Acyclic retinoid in the chemoprevention of hepatocellular carcinoma (review). 1501 Aug 15

The severity of hepatocellular carcinoma (HCC) and the lack of good diagnostic markers and treatment strategies have rendered the disease a major challenge. Previous microarray analyses of HCC were restricted to the selected tissue sample sets without validation on an independent series of tissue samples. We describe an approach to the identification of a composite discriminator cassette by intersecting different microarray datasets. We studied the global transcriptional profiles of matched HCC tumor and nontumor liver samples from 37 patients using cDNA (cDNA) microarrays. Application of nonparametric Wilcoxon statistical analyses (P < 1 x 10(-6)) and the criteria of 1.5-fold differential gene expression change resulted in the identification of 218 genes, including BMI-1, ERBB3, and those involved in the ubiquitin-proteasome pathway. Elevated ERBB2 and epidermal growth factor receptor (EGFR) expression levels were detected in ERBB3-expressing tumors, suggesting the presence of ERBB3 cognate partners. Comparison of our dataset with an earlier study of approximately 150 tissue sets identified multiple overlapping discriminator markers, suggesting good concordance of data despite differences in patient populations and technology platforms. These overlapping discriminator markers could distinguish HCC tumor from nontumor liver samples with reasonable precision and the features were unlikely to appear by chance, as measured by Monte Carlo simulations. More significantly, validation of the discriminator cassettes on an independent set of 58 liver biopsy specimens yielded greater than 93% prediction accuracy. In conclusion, these data indicate the robustness of expression profiling in marker discovery using limited patient tissue specimens as well as identify novel genes that are highly likely to be excellent markers for HCC diagnosis and treatment.
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PMID:Identification of discriminators of hepatoma by gene expression profiling using a minimal dataset approach. 1505 98

Proteasome inhibitors, like MG132, can exert cell growth inhibitory and apoptotic effects in different tumor types. The apoptotic mechanism of these compounds involves the activation of the effector caspases. beta-catenin, also an oncogene, represents one of the substrates of these proteases, but the consequences of its cleavage are poorly understood. We investigated its function during apoptosis induced by MG132 in three hepatocellular carcinoma (HCC) cell lines, endowed (HepG2 and HuH-6) or not (HA22T/VGH) with activating mutations of beta-catenin. Induction of apoptosis was associated with cell growth inhibition, accumulation of the cells at the G(2)/M phases of the cell cycle, as well as with fragmentation of beta-catenin (but not of alpha- or gamma-catenin) in all the cell lines. The cleavage of beta-catenin was inhibited by the caspase inhibitors Z-VAD-fmk and Z-DEVD-fmk. Fragmented beta-catenin was found in the nuclei of the treated cells. Analyses through the reporter plasmid pTOPflash showed that MG132 significantly reduces Tcf transcriptional activity in the cells. This was associated with a decrease in the mRNA expression of survivin and c-myc, which are target genes of the APC/beta-catenin/Tcf signaling. Nevertheless, Z-VAD-fmk or Z-DEVD-fmk did not reverse the MG132 effects on Tcf transcriptional activity, suggesting that the compound may affect this activity also by other mechanisms. Overall, the present study supports the therapeutic potential of the proteasome inhibitors in HCC.
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PMID:Induction of apoptosis by the proteasome inhibitor MG132 in human HCC cells: Possible correlation with specific caspase-dependent cleavage of beta-catenin and inhibition of beta-catenin-mediated transactivation. 1506 80


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