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)

Proteins expressed by plasmids encoding human cyclins and cyclin-dependent kinase 2 (CDK2) were used as antigens in immunoblotting. Fifteen of 100 patients with hepatocellular carcinoma (HCC) were found to have autoantibodies reactive with cyclin B1 and with a 40-kd degradation product of cyclin B1-glutathione-S-transferase (GST) fusion protein. Only one serum was found to react with cyclin A and another single serum with CDK2 but no antibodies were detected to cyclin D1 and E. The basis for autoimmune responses to cyclin B1 in HCC are unknown at the present time but the possibilities might include aberrations in cyclin B1 regulation leading to altered product or its expression which resulted in stimulation of immune reactions.
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PMID:Immune response to cyclin B1 in hepatocellular carcinoma. 898 68

Cyclin B1 is a key regulatory protein involved in cellular mitosis. We have cloned 1.8kb of DNA sequence upstream of the rat cyclin B1 gene translation start site from Rattus norvegicus liver genomic DNA and a commercial rat testis genomic library. The mRNA transcription start point (tsp) was determined by primer extension and mRNA end ligation followed by RT-PCR across the ligated 3' and 5' ends. An authentic tsp was confirmed approximately 100bp upstream of the translation start site. A second potential tsp was also detected approximately 32bp downstream from the first. RT-PCR analysis of rat liver poly(A)(+) RNA using 5'-derived oligonucleotide primers indicated that the 5' end sequence was present in both the 1.6 and 2. 4kb rat liver cyclin B1 mRNA species. Like many other cyclin promoters, there was no apparent TATA box upstream of the transcription initiation sites. However, computer analysis of the promoter region identified a group of consensus transcription factor binding sites, some of which are also reported in other cyclin promoters. These include those for p53, p21, Ap-1, Ap-2, Ets-1, CAATT, E-Box and Yi. We also performed luciferase reporter assays using a set of promoter deletion constructs in human HuH-7 hepatoma and HeLa carcinoma cell lines. Our results suggest that an E-Box and/or CCAAT binding sites are important for transcription, and that there may be negative regulatory elements present between 1800 and 1100bp upstream of the translation start site.
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PMID:Genomic organization and promoter characterization of the rat cyclin B1 gene. 1097 69

The forkhead box (Fox) family of transcription factors share homology in the winged helix/forkhead DNA-binding domain and play important roles in regulating cellular proliferation, differentiation, longevity, and cellular transformation. Forkhead box M1B (FoxM1B) is a ubiquitously expressed member of the Fox transcription factor family whose expression is restricted to proliferating cells and that mediates hepatocyte entry into DNA synthesis and mitosis during liver regeneration. Recent cDNA microarray studies indicated that age-related defects in cellular proliferation are associated with diminished expression of the FoxM1B transcription factor. Here, we show that increased levels of FoxM1B in regenerating liver of old transgenic mice restore the sharp peaks in hepatocyte DNA replication and mitosis that are the hallmarks of young regenerating mouse liver. Restoration of the young regenerating liver phenotype is associated with increased expression of numerous cell cycle regulatory genes that include cyclin D1, cyclin A2, cyclin F, cyclin B1, cyclin B2, Cdc25B, and p55cdc. Cotransfection assays in the human hepatoma HepG2 cell line demonstrated that FoxM1B protein stimulated expression of both the cyclin B1 and cyclin D1 promoters, suggesting that these cyclin genes are a direct FoxM1B transcriptional target. These results suggest that FoxM1B controls the transcriptional network of genes that are essential for cell division and exit from mitosis. Our results indicate that reduced expression of the FoxM1B transcription factor contributes to the decline in cellular proliferation observed in the aging process.
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PMID:Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver. 1157 93

Aberrant activation of Wnt signaling caused by mutations in adenomatous polyposis coli (APC) or beta-catenin is a critical event in the development of human colorectal tumors. Wnt signaling stabilizes beta-catenin, which in turn associates with TCF/LEF family transcription factors, ultimately altering the expression of Wnt target genes. We have recently identified ICAT, a beta-catenin-interacting protein that interferes with the interaction between beta-catenin and TCF-4, thereby negatively regulating Wnt signaling. In the present study, we generated a recombinant adenovirus encoding ICAT and examined its effect on the growth of tumor cells. We found that Icat inhibits proliferation of colorectal tumor cells mutated in APC or beta-catenin and hepatocellular carcinoma cells mutated in AXIN: By contrast, Icat did not inhibit growth of either normal or tumor cells containing the wild-type APC, beta-catenin, and Axin genes. Icat also inhibited the anchorage-independent growth of colorectal tumor cells and tumorigenic growth of colorectal tumor xenografts. Furthermore, we found that Icat inhibits both dephosphorylation of Cdc2 and nuclear translocation of cyclin B1 and induces G(2) arrest followed by cell death in colorectal tumor cells. These results suggest that Wnt signaling is critical for the growth of colorectal tumors and some hepatocellular carcinomas and that expression of ICAT or drugs which mimic its effects may be useful in the treatment of these tumors.
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PMID:Overexpression of Icat induces G(2) arrest and cell death in tumor cell mutants for adenomatous polyposis coli, beta-catenin, or Axin. 1203 51

NCTD is a demethylated form of cantharidin with antitumor properties, which is now in use as a routine anticancer drug against hepatoma. However, there is limited information on the effect of NCTD on human cancer cells. In the present study, NCTD inhibited proliferation, caused mitotic arrest, then progressed to apoptosis within 96 hr in 3 human hepatoma cell lines: HepG2, Hep3B and Huh-7. NCTD treatment (5 microg/ml) enhanced the expression of Cdc25C and p21(Cip1/Waf1), increasing the phosphorylation of these 2 proteins. In addition, NCTD treatment induced an earlier increase in cyclin B1-associated histone H1 kinase activity within 48 hr, but an approximately 70% reduction of both protein level and kinase activity of cyclin B1 was observed at 72 hr. Treatment with NCTD significantly decreased the expression of p53 protein but did not affect the expression of Cdk1 and p27(Kip1). Moreover, NCTD treatment also increased the phosphorylation of Bcl-2 and Bcl-X(L) but did not affect the expression of Bax or Bad. Bcl-2 phosphorylation appears to inhibit its binding to Bax since less Bax was detected in immunocomplex with Bcl-2 in NCTD-treated HepG2 cells. In addition, NCTD treatment caused activation of caspase-9 and caspase-3, preceding DNA fragmentation and morphologic features of apoptosis. Pretreatment with the broad-spectrum caspase inhibitor z-VAD-fmk markedly inhibited NCTD-induced caspase-3 activity and cell death. These results suggest that phosphorylation of p21(Cip1/Waf1) and Cdc25C and biphasic regulation of cyclin B1-associated kinase activity may contribute to NCTD-induced M-phase cell-cycle arrest. Furthermore, the increase of p21(Cip1/Waf1), phosphorylation of Bcl-2 and Bcl-X(L), activation of caspase-9 and caspase-3 may be the molecular mechanism through which NCTD induces apoptosis.
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PMID:Effector mechanisms of norcantharidin-induced mitotic arrest and apoptosis in human hepatoma cells. 1211 64

A comparison was made between two K vitamin analogs. Growth in vitro of Hep G2 hepatoma cells was inhibited both by Compound 5 (Cpd 5), a recently synthesized thioalkyl analog of vitamin K or 2-(2-mercaptoethanol)-3-methyl-1, 4-naphthoquinone, as well as by synthetic vitamin K3 (menadione). Using synchronized Hep G2 hepatoma cells, the actions of both Cpd 5 and vitamin K3 on cell cycle regulating proteins were examined. Cpd 5 decreased the levels of cyclin D1, Cdk4, p16, p21 and cyclin B1. By contrast, VK3 only decreased the level of cyclin D1, but had no effect on the levels of Cdk4, p16 or p21. Interestingly, both VK3 and VK2 increased the levels of p21. The naturally occurring K vitamins had little effect on cell growth and none on the cyclins or Cdks. Amounts and activity of the G1/S phase controlling Cdc25A were measured. We found that Cpd 5 directly inhibited both Cdc25A activity and its protein expression, whereas VK3 did not. Thus, the main effects of Cpd 5 were on G1 and S phase proteins, especially Cdk4 and Cdc25A amounts in contrast to VK3. Computer docking studies of Cpd 5 and VK3 to Cdc25A phosphatase showed three binding sites. In the best conformation, Cpd 5 was found to be closer to the enzyme active site than VK3. These findings show that Cpd 5 represents a new class of anticancer agent, being a protein tyrosine phosphatase (PTP) antagonist, that binds to Cdc25A with suppression of its activity. Tumors expressing high levels of oncogenic Cdc25A phosphatase may thus be susceptible to the growth inhibitory activities of this class of compound.
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PMID:Differential effects of two growth inhibitory K vitamin analogs on cell cycle regulating proteins in human hepatoma cells. 1267 93

3-Bromopropionylamino benzoylurea (JIMB01) is a small molecular weight compound (MW 313) that has been synthesized in our laboratory. This compound showed antiproliferative activities in a panel of thirteen human tumor cell lines with IC(50) values in the range of 0.25 to 0.51 micro M for leukemia and lymphoma cell lines and 0.33 to 9.26 micro M for solid tumor cell lines. The primary action of JIMB01 is to inhibit microtubule polymerization but not depolymerization. A 4 micro M concentration of the compound caused a complete inhibition of microtubule assembly in a cell-free reaction. An increase in the number of human hepatocarcinoma cells blocked in the M-phase was detected 12hr after exposure to JIMB01. The kinase activity of cyclin B1, which is responsible for the G(2)/M transition, was increased accordingly. Bcl-2 phosphorylation became visible, in a western blot, within 6hr in hepatocarcinoma cells treated with JIMB01 at 0.8 micro M or higher. JIMB01-induced apoptosis in liver cancer cells was confirmed by morphological methods, flow cytometry, as well as DNA gel electrophoresis, which clearly demonstrated DNA degradation in the form of a multiple-unit DNA ladder. Furthermore, in vivo experiments using nude mice showed that intraperitoneal injection of JIMB01 at 15mg/kg (with seven injections at 4-day intervals) significantly inhibited the growth of a human hepatocarcinoma (BEL-7402) by 66% in tumor volume (P=0.01), at least compatible to the inhibition by vincristine (43% inhibition), indicating good bioavailability of the compound in the circulation. Side-effects of the compound were not observed, and the body weight of the treated mice remained stable during the 4-week treatment. Since JIMB01 is a small compound, targets a specific molecule in tumor cells, and has promising activity against human hepatocarcinoma in vivo, we believe JIMB01 merits consideration for further investigation.
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PMID:Inhibition of microtubule polymerization by 3-bromopropionylamino benzoylurea (JIMB01), a new cancericidal tubulin ligand. 1275 5

The chemopreventive role of 5-methoxypsoralen (5-MOP) in the human hepatocellular carcinoma (HCC) cell line was investigated by studying the regulation of proliferation and apoptosis in HCC (J5) cells. Morphological analysis, cell viability assay, DNA analysis and cell-cycle analysis suggest that there are at least three modes of the suppressive effects shown by 5-MOP: (a) kills J5 cells directly; (b) induces apoptosis by arresting J5 cells at the G2/M phase in the cell cycle; (c) induces apoptosis through an independent pathway with cell-cycle arrest at 24-72 h of exposure. Further immunoblot analysis demonstrated that inhibition of cyclin B1 by 5-MOP may play an important role in G2/M arrest of J5 cells and provides an additional way to prevent cells from entering the M phase and undergoing apoptosis. 5-MOP therefore appears to exert its anticarcinogenic properties by cytotoxic effect, inducing apoptosis and inhibiting proliferation in the human hepatocellular carcinoma cell line.
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PMID:Effect of 5-methoxypsoralen (5-MOP) on cell apoptosis and cell cycle in human hepatocellular carcinoma cell line. 1278 Dec 6

beta-Phenylethyl isothiocyanate (PEITC) is a promising chemoprotective compound that is routinely consumed in the diet as its glucosinolate precursor. Previous studies have shown that PEITC can inhibit phase I enzymes and induce phase II detoxification enzymes along with apoptosis in vitro. The detailed mechanisms involved in the apoptotic cascade, however, have not been elucidated. In the present study, we demonstrate that PEITC can induce apoptosis in hepatoma HepG2 cells in a concentration- and time-dependant manner as determined by TUNEL positive and SubG1 population analysis. Caspase-3-like activity and poly(ADP-ribosyl)polymerase cleavage increased during treatment with 20 microM PEITC; high concentrations, however, induced necrosis. Pre-treatment with Z-VAD-FMK and the caspase-3-specific inhibitor Ac-DEVD-CHO prevented PEITC-induced apoptosis, as determined by caspase-3-like activity and DNA fragmentation. Additional investigations also showed that at concentrations of 5-10 microM PEITC, DNA synthesis was inhibited and G2/M phase cell cycle arrest occurred, correlating with an alteration in cyclin B1 and p34(cdc2) protein levels. Furthermore, we also demonstrate a concentration- and time-dependant burst of superoxide (O2*-) in PEITC-treated cells. However, pre- and co-treatment with the free radical scavengers Trolox, ascorbate, mannitol, uric acid and the superoxide mimetic manganese (III) tetrakis (N-methyl-2-pyridyl) porphyrin failed to prevent PEITC-mediated apoptosis. Taken together, these results suggest that PEITC potently induces apoptosis and cell cycle arrest in HepG2 cells and that the generation of reactive oxygen species appears to be a secondary effect.
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PMID:beta-Phenylethyl isothiocyanate-mediated apoptosis in hepatoma HepG2 cells. 1294 35

Recent studies have shown that selective cyclooxygenase-2 (COX-2) inhibitors induce growth inhibition and cell cycle arrest in hepatocellular carcinoma (HCC) cell lines. However, the mechanism by which COX-2 inhibitors regulate the cell cycle and whether or not growth signal pathways are involved in the growth inhibition remain unclear. In this study, we investigated the mechanisms of growth inhibition and cell cycle arrest by etodolac, a selective COX-2 inhibitor, in HCC cell lines, HepG2 and PLC/PRF/5, by studying cell cycle regulatory proteins, and the MAP kinase and PDK1-PKB/AKT signaling pathways. Etodolac inhibited growth and PCNA expression and induced cell cycle arrest in both HCC cell lines. Etodolac induced p21WAF1/Cip1 and p27Kip1 expression and inhibited CDK2, CDK4, CDC2, cyclin A and cyclin B1 expression, but did not affect cyclin D1 or cyclin E. HGF and 10% FBS induced ERK phosphorylation, but phosphorylation of p38, JNK and AKT was down-regulated by etodolac. PD98059, a selective inhibitor of ERK phosphorylation, induced growth inhibition, the expression of p27Kip1 and cell cycle arrest. In conclusion, p21WAF1/Cip1, p27Kip1, CDK2, CDK4, CDC2, cyclin A, cyclin B1 and the MAP kinase signaling pathway are involved in growth inhibition and cell cycle arrest by a selective COX-2 inhibitor in HCC cell lines.
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PMID:Involvement of cell cycle regulatory proteins and MAP kinase signaling pathway in growth inhibition and cell cycle arrest by a selective cyclooxygenase 2 inhibitor, etodolac, in human hepatocellular carcinoma cell lines. 1529 30


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