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)

Cachexia is a debilitating syndrome characterized by body weight loss, muscle wasting, and anemia. Muscle wasting results from an altered balance between protein synthesis and degradation rates. Reactive oxygen species are indicated as crucial players in the onset of muscle protein hypercatabolism by upregulating elements of the ubiquitin-proteasome pathway. The present study has been aimed at evaluating comparatively the involvement of oxidative stress in the pathogenesis of skeletal muscle wasting in two different experimental models: rats rendered hyperglycemic by treatment with streptozotocin and rats bearing the Yoshida AH-130 ascites hepatoma. For this purpose, both tumor bearers and diabetic animals have been treated with dehydroepiandrosterone (DHEA), a multifunctional steroid endowed with multitargeted antioxidant properties. We show that diabetic rats and AH-130 rats share several features, hypoinsulinemia, occurrence of oxidative stress, and positive response to DHEA administration, although the extent of the effects of DHEA largely differs between diabetic animals and tumor-bearing rats. The hypercatabolism, evaluated in terms of proteasome activity and expression of atrogin-1 and MuRF1, is activated in AH-130 rats, whereas it is lacking in streptozotocin-treated rats. Moreover, we demonstrate that the role of oxidative stress can interfere with muscle wasting through different mechanisms, not necessarily involving NF-kappaB activation. In conclusion, the present results show that, although skeletal muscle wasting occurs in both diabetic rats and tumor-host rats, the underlying mechanisms are different. Moreover, despite oxidative stress being detectable in both experimental models, its contribution to muscle wasting is not comparable.
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PMID:Muscle wasting in diabetic and in tumor-bearing rats: role of oxidative stress. 1805 17

Recent studies have demonstrated that aldo-keto reductase family 1 B10 (AKR1B10), a novel protein overexpressed in human hepatocellular carcinoma and non-small cell lung carcinoma, may facilitate cancer cell growth by detoxifying intracellular reactive carbonyls. This study presents a novel function of AKR1B10 in tumorigenic mammary epithelial cells (RAO-3), regulating fatty acid synthesis. In RAO-3 cells, Sephacryl-S 300 gel filtration and DEAE-Sepharose ion exchange chromatography demonstrated that AKR1B10 exists in two distinct forms, monomers (approximately 40 kDa) bound to DEAE-Sepharose column and protein complexes (approximately 300 kDa) remaining in flow-through. Co-immunoprecipitation with AKR1B10 antibody and protein mass spectrometry analysis identified that AKR1B10 associates with acetyl-CoA carboxylase-alpha (ACCA), a rate-limiting enzyme of de novo fatty acid synthesis. This association between AKR1B10 and ACCA proteins was further confirmed by co-immunoprecipitation with ACCA antibody and pulldown assays with recombinant AKR1B10 protein. Intracellular fluorescent studies showed that AKR1B10 and ACCA proteins co-localize in the cytoplasm of RAO-3 cells. More interestingly, small interfering RNA-mediated AKR1B10 knock down increased ACCA degradation through ubiquitination-proteasome pathway and resulted in >50% decrease of fatty acid synthesis in RAO-3 cells. These data suggest that AKR1B10 is a novel regulator of the biosynthesis of fatty acid, an essential component of the cell membrane, in breast cancer cells.
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PMID:Aldo-keto reductase family 1 B10 affects fatty acid synthesis by regulating the stability of acetyl-CoA carboxylase-alpha in breast cancer cells. 1805 16

LEC rats show spontaneous hepatitis and hepatocarcinoma development related to oxidative stress due to abnormal copper accumulation in the liver. We used DNA microarrays bearing 22,012 genes to investigate at the transcriptomic level the progression of the hepatitis in LEC rats in comparison to a control obtained from LEC rats treated with D-penicillamine, a copper chelating agent known to block hepatitis development. Multivariate statistical analyses as partial least square (PLS) regression between transcriptomic data and hepatitis markers in plasma led us to select 483 genes related to hepatitis development in these rats. After a complementary discriminant analysis (PLS-DA), 239 important genes for the separation between the different rat groups were selected. Gene ontology classification revealed an overrepresentation of genes involved in protein metabolism-related functions. More importantly, some genes implicated in proteasome pathway were upregulated. However, analysis of 20S proteasome activity showed that trypsin-like and peptidylglutamyl peptide hydrolase activities were diminished during hepatitis. Because oxidative stress is known to promote the inactivation of the proteasome complex, we propose the deregulation of the proteasome genes expression as a result of oxidative inactivation of proteasome activity during hepatitis in LEC rats. These results bring new insights in the hepatitis and the hepatocarcinogenesis development.
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PMID:Proteasome activity deregulation in LEC rat hepatitis: following the insights of transcriptomic analysis. 1809 9

The hepatitis B virus X protein (HBX) plays key regulatory roles in viral replication and the development of hepatocellular carcinoma. HBX is an unstable protein; its instability is attributed to rapid degradation through the ubiquitin-proteasome pathway. Here, we show that the middle and carboxyl-terminal domains of HBX, independently fused to GFP, render the recombinant proteins susceptible to proteasomal degradation, while the amino-terminal domain has little effect on the ubiquitination or stability of HBX. Mutation of any single or combination of up to five of six lysine residues, all located in the middle and carboxyl-terminal domain, did not prevent HBX from being ubiquitinated, ruling out any specific lysine as the sole site of ubiquitination. Surprisingly, HBX in which all six lysines were mutated and showed no evidence of ubiquitination, was still susceptible to proteasomal degradation. These results suggest that both ubiquitin-dependent and -independent proteasomal degradation processes are operative in HBX turnover.
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PMID:Ubiquitin-dependent and -independent proteasomal degradation of hepatitis B virus X protein. 1815 58

Fucoxanthin, a major carotenoid in brown sea algae, has recently been demonstrated by us to inhibit the proliferation of colon cancer cells, and this effect was associated with growth arrest. These results, taken together with previous studies with fucoxanthin, suggest that it may be useful in chemoprevention of other human malignancies. The present study was designed to evaluate the molecular mechanisms of fucoxanthin against hepatic cancer using the human hepatocarcinoma HepG2 cell line (HepG2). Fucoxanthin reduced the viability of HepG2 cells accompanied with the induction of cell cycle arrest during the G0/G1 phase at 25 microM. This concentration of fucoxanthin inhibited the phosphorylation of the retinoblastoma protein (Rb) at Serine 780 (Ser780) position 18 h after treatment. The kinase activity of cyclin D and cdk4 complex, responsible for the phosphorylation of Rb Ser780 site, was down-regulated 18 h after the treatment. Western blotting analysis revealed that the expression of cyclin D-type protein was suppressed by treatment of fucoxanthin. This reduction was partially blocked by concurrent treatment with the proteasome inhibitor MG132, indicating the involvement of the proteasome-mediated degradation. In addition, RT-PCR analysis revealed that fucoxanthin also appeared to repress cyclin D mRNA. Thus, both the protein degradation and transcriptional repression seem to be responsible for suppressed cyclin D level in fucoxanthin-treated HepG2 cells which may be related to the antitumorgenic activity.
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PMID:Growth inhibition of human hepatic carcinoma HepG2 cells by fucoxanthin is associated with down-regulation of cyclin D. 1823 Mar 64

A series of peptidyl vinyl ester derivatives bearing three different P1 substitutions as potential proteasome inhibitors were studied. The target molecules were designed based on CADD (computer aided drug design) protocol and synthesized. Their activities toward proteasome and four human cancer cell lines (including hepatoma cell line (Bel-7402), myeloid leukemic cell line (HL-60), gastric cancer cell line (BGC-823) and nasopharyngeal cancer cell line (KB)) were tested using fluorescence assay. Two compounds showed proteasome inhibitory activities, and four compounds showed weak antiproliferative activities toward HL-60 and BGC-823.
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PMID:Novel CADD-based peptidyl vinyl ester derivatives as potential proteasome inhibitors. 1828 Jan 55

Survivin is an attractive target in cancer therapy. Previous studies have demonstrated that survivin dominant-negative mutants T34A and C84A were able to induce apoptosis in cancer cells. Given that they had different mechanisms in inducing apoptosis, our study was undertaken to determine whether a survivin double point mutant (TC34,84AA) could achieve more potent inhibitory effect on the growth of hepatocellular cancer cells. Adenoviruses expressing survivin mutants were constructed and transduced into hepatocellular cancer cells. The inhibitory effect of the survivin mutants on cancer cell growth was measured. Transduction of cancer cells with all three survivin mutants resulted in significant apoptosis. Compared with survivin mutants T34A or C84A alone, the cancer killing effect of survivin TC34,84AA was much stronger. In addition, the survivin mutants were more sensitive than wild type survivin to the degradation in the ubiquitin-proteasome pathway. Our results suggest that adenovirus-delivered dominant-negative survivin TC34,84AA promotes apoptosis-mediated hepatocellular carcinoma suppression, and could potentially be a promising candidate for cancer therapies.
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PMID:A survivin double point mutant has potent inhibitory effect on the growth of hepatocellular cancer cells. 1836 66

Hepatitis C virus (HCV) is a major cause of chronic liver diseases, including steatosis, cirrhosis and hepatocellular carcinoma, and epidemiological studies indicate that HCV is also associated with insulin resistance and type 2 diabetes mellitus. The HCV core protein is not only a viral structural component but also a pathogenic factor, since its expression leads to the development of liver steatosis, insulin resistance and hepatocellular carcinoma in mice. The nuclear proteasome activator PA28gamma/REGgamma, which specifically binds to the core protein, is required for the virulence of the core protein. Elucidation of the mechanisms by which HCV core protein participates in the above conditions may provide clues toward the development of novel therapeutic measures for chronic hepatitis C.
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PMID:Hepatitis C virus core protein: its coordinate roles with PA28gamma in metabolic abnormality and carcinogenicity in the liver. 1832 62

Heme oxygenase 1 (HO-1) is the first and rate-controlling enzyme in heme degradation. Bach1 is a mammalian transcriptional repressor of HO-1. To understand how zinc mesoporphyrin (ZnMP) induces the expression of HO-1, we investigated the effects of ZnMP on Bach1 mRNA and protein levels in human hepatoma Huh-7 cells by quantitative RT-PCR and Western blots. We found that ZnMP markedly up-regulated HO-1 mRNA and protein levels, and rapidly and significantly decreased Bach1 protein levels by increasing degradation of Bach1 protein [half life (t(1/2)) from 19 h to 45 min], whereas ZnMP did not influence Bach1 mRNA levels. The proteasome inhibitors, epoxomicin and MG132, significantly inhibited degradation of Bach1 by ZnMP in a dose-dependent fashion, indicating that the degradation of Bach1 by ZnMP is proteasome-dependent. Purified Bach1 C-terminal fragment bound heme, but there was no evidence for binding of ZnMP to the heme-binding region of Bach1. In conclusion, ZnMP produces profound post-transcriptional down-regulation of Bach1 protein levels and transcriptional up-regulation of HO-1. Our results indicate that ZnMP up-regulates HO-1 gene expression by markedly increasing Bach1 protein degradation in a proteasome-dependent manner.
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PMID:Zinc mesoporphyrin induces rapid and marked degradation of the transcription factor Bach1 and up-regulates HO-1. 1832 50

The ATPase associated with various cellular activities (AAA-ATPase) p97 (p97) has been implicated in the retrotranslocation of target proteins for delivery to the cytosolic proteasome during endoplasmic reticulum-associated degradation (ERAD). Apolipoprotein B-100 (apoB-100) is an ERAD substrate in liver cells, including the human hepatoma, HepG2. We studied the potential role of p97 in the ERAD of apoB-100 in HepG2 cells using cell permeabilization, coimmunoprecipitation, and gene silencing. Degradation was abolished when HepG2 cytosol was removed by digitonin permeabilization, and treatment of intact cells with the proteasome inhibitor MG132 caused accumulation of ubiquitinated apoB protein in the cytosol. Cross-linking of intact cells with the thiol-cleavable agent dithiobis(succinimidylpropionate) (DSP), as well as nondenaturing immunoprecipitation, demonstrated an interaction between p97 and intracellular apoB. Small interfering ribonucleic acid (siRNA)-mediated reduction of p97 protein increased the intracellular levels of newly synthesized apoB-100, predominantly because of a decrease in the turnover of newly synthesized apoB-100 protein. However, although the posttranslational degradation of newly synthesized apoB-100 was delayed by p97 knockdown, secretion of apoB-100 was not affected. Knockdown of p97 also impaired the release of apoB-100 and polyubiquitinated apoB into the cytosol. In summary, our results suggest that retrotranslocation and proteasomal degradation of apoB-100 can be dissociated in HepG2 cells, and that the AAA-ATPase p97 is involved in the removal of full-length apoB from the biosynthetic pathway to the cytosolic proteasome.
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PMID:The AAA-ATPase p97 facilitates degradation of apolipoprotein B by the ubiquitin-proteasome pathway. 1855 Aug 91


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