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)

LIGHT is a member of the tumor necrosis factor superfamily and is the ligand for LT-betaR, HVEM, and decoy receptor 3. LIGHT has a cytotoxic effect, which is further enhanced by the presence of interferon-gamma (IFN-gamma). Although LIGHT/IFN-gamma can activate caspase activity, neither benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone nor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone can completely inhibit LIGHT/IFN-gamma-mediated apoptosis. Moreover, overexpression of Bcl-2 further enhances LIGHT/IFN-gamma-mediated apoptosis. It appears that LIGHT and IFN-gamma act synergistically to activate caspase-3, with the resultant cleavage of Bcl-2, removal of the BH4 domain, leading to conversion of Bcl-2 from an antiapoptotic to a proapoptotic form in p53-deficient hepatocellular carcinoma Hep3BT2 cells. Thus, LIGHT seems to be able to override the protective effect of Bcl-2 and induce cell death. Although benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone can prevent the cleavage of Bcl-2 by LIGHT/IFN-gamma, they only partially inhibit apoptosis in Hep3BT2 cells that are overexpressing Bcl-2. In contrast, both LIGHT/IFN-gamma-mediated apoptosis and Bcl-2 cleavage are inhibited by free radical scavengers, indicating that free radicals may play an essential role in LIGHT/IFN-gamma-mediated apoptosis at a step upstream of caspase-3 activation. These results suggest that LIGHT signaling may diverge into multiple, separate processes.
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PMID:Overexpression of bcl-2 enhances LIGHT- and interferon-gamma -mediated apoptosis in Hep3BT2 cells. 1099 81

Polychlorinatedbiphenyls (PCBs) are a group of persistent and widely dispersed environmental pollutants, some of which may be immunotoxic. In the present study, we investigated the effect of PCBs on immune system by assessing apoptotic cell death in human monocytic U937 cells. Among the various congeners tested, 2,2',4,6, 6'-pentachlorobiphenyl (PeCB), a highly ortho-substituted congener, specifically induced DNA fragmentation, a hallmark of apoptosis, while the other examined di-, tri-, tetra-, and pentachlorobiphenyls did not. To further study the 2,2',4,6,6'-PeCB-induced cell death, various features of apoptosis were examined. 2,2',4,6,6'-PeCB caused a decrease in cell viability and induced cellular morphologic features characteristic of apoptosis such as chromatin aggregation and apoptotic bodies. In addition, caspase-3, an executioner of apoptosis, was activated and its substrate, poly(ADP-ribose) polymerase (PARP), was cleaved during 2,2',4,6,6'-PeCB-induced apoptosis. In contrast, 3,3',4,4',5-PeCB, a congener of coplanar structure, as well as 2,3,7,8-TCDD did not induce apoptosis in these human monocytic cells, although they potently induced CYP 1A1 in human hepatoma Hep G2 cells. Taken together, the data indicate that 2,2',4,6,6'-PeCB induces apoptosis in human monocytic cells through a mechanism that is independent of the arylhydrocarbon receptor. This suggests a possibly separate mechanism by which PCBs cause immunosuppression.
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PMID:2,2',4,6,6'-pentachlorobiphenyl induces apoptosis in human monocytic cells. 1107 90

The aim of this study was to investigate whether there was a particular hepatitis B virus (HBV) X protein (HBx) mutant associated with Taiwanese patients with hepatocellular carcinoma (HCC). Initially, the entire coding region of HBx gene from the serum samples of 14 Taiwanese patients were sequenced. A novel mutant, HBx-A31, was preferentially found in patients with HCC. Sera from 67 patients with HCC and 100 patients with chronic hepatitis B were thus subjected for codon 31 analysis using a dual amplification created restriction site method. HBx-A31 was detected more frequently in patients with HCC (52% versus 12%; P<0.001) and in patients with liver cirrhosis (44% versus 6%; P<0.001). Site directed mutagenesis experiment revealed that HBx-A31 was less effective in transactivating HBV enhancer I-X promoter complex, less efficient in supporting HBV replication, and less potent in enhancing TNF-alpha induced increment of CPP32/caspase 3 activities in HepG2 cells. In conclusion, a prevalent HBx mutant was identified in Taiwanese patients with hepatocellular carcinoma. Development of this mutant might represent a strategy of the virus to escape immune surveillance and thus contribute to the process of multiple-step hepatocarcinogenesis.
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PMID:Identification and characterization of a prevalent hepatitis B virus X protein mutant in Taiwanese patients with hepatocellular carcinoma. 1107 37

10-Hydroxycamptothecin (HCPT), a DNA topoisomerase I (Topo I) inhibitor, exhibited a remarkable apoptosis-inducing effect on human hepatoma Hep G2 cells. We studied the effect of HCPT upon the expression of P53, c-Myc, Bcl-2, Bax and alpha-fetoprotein (AFP) proteins, and caspase (caspase-1 and caspase-3) activity of Hep G2 cells. It showed that HCPT at a dose of 0.1 microg/ml increased the expression of P53, c-Myc and Bax protein, and decreased the expression of Bcl-2 and AFP. The increase of P53, which was remarkable after only 3 h incubation with HCPT, occurred much earlier than the changes of other proteins, suggesting that the increase of P53 expression may be the upstream event in the apoptosis of Hep G2 cells induced by HCPT. Both caspase-1 and caspase-3 were activated in Hep G2 cells by HCPT treatment, suggesting that caspase-1 and caspase-3 are involved in the process of apoptosis in Hep G2 cells, and may be the main effectors of the apoptosis.
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PMID:Differential regulation of P53, c-Myc, Bcl-2, Bax and AFP protein expression, and caspase activity during 10-hydroxycamptothecin-induced apoptosis in Hep G2 cells. 1112 38

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

Ursodeoxycholic acid (UDCA) protects cells from the apoptotic effects of hydrophobic bile acids and some other cytotoxic agents. We observed the opposite result when assessing the effects of UDCA on the apoptotic response to mitochondrial photodamage induced by photodynamic therapy (PDT). Two photosensitizers with predominantly mitochondrial specificity were used: a porphycene we have designated CPO; and the tin etiopurpurin SnET2. UDCA potentiated the loss of mitochondrial potential, release of cytochrome c into the cytosol, activation of caspase-3, and apoptotic cell death after irradiation of photosensitized murine leukemia L1210 or hepatoma 1c1c7 cells. These effects were not observed when UDCA was added after irradiation. Glyco-UDCA and tauro-UDCA, conjugated forms of UDCA that are formed in vivo, were as effective as UDCA in promoting PDT phototoxicity. Because UDCA does not act by enhancing intracellular accumulation of the photosensitizing agents used in this study, we propose that the mode of action of UDCA involves the sensitization of mitochondrial membranes to photodamage. UDCA is used currently in gastroenterology for several indications. The drug may offer a means for promoting the efficacy of PDT with minimal adverse effects.
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PMID:Potentiation of photodynamic therapy by ursodeoxycholic acid. 1115

The objective of this study was to establish whether apoptosis in 5123tc rat hepatoma cells required the caspase-3 dependent pathway. Apoptosis was induced by either growth factor deprivation or treatment with a topoisomerase II inhibitor, VM26, in the absence or presence of caspase inhibitors (DEVD-fmk, z-VAD-fmk and BAF). The results indicated that, although these inhibitors at 10 microM concentration completely blocked caspase-3 activity, they had no effect on either the rate of cell death or on any other apoptotic features, e.g., chromatin condensation, DNA fragmentation, protein cleavage, suggesting that caspase-3 was not required to mediate nuclear destruction in these hepatoma cells. At higher concentrations, up to 100 microM, z-VAD-fmk and BAF, but not DEVD-fmk, did block apoptosis, however, they also caused cell swelling and membrane permeabilization, which are the hallmarks of necrotic cell death. Clearly, high concentrations of these inhibitors must have interfered non-specifically with other metabolic pathways, e.g., z-VAD-fmk at a high concentration blocked protein phosphorylation, and caused cell death by a different mechanism.
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PMID:Caspase-dependent and independent cell death in rat hepatoma 5123tc cells. 1122 48

Hepatocellular carcinoma is one of the most lethal malignancies and there is no effective preventive measure in this highly malignant disease to date. In the present study, we investigated the chemopreventive potential of capsaicin (8-methyl-N- vanillyl-6-nonenamide), the principal pungent ingredient found in hot red pepper, in SK-Hep-1 hepatocellular carcinoma cells. Treatment of capsaicin inhibited growth of SK-Hep-1 cells in a concentration-dependent manner while 4-methoxy capsaicin (Met-capsaicin) was less potent. This inhibitory effect of capsaicin on SK-Hep-1 cell growth was mainly due to the induction of apoptosis as evidenced by DNA fragmentation and nuclear condensation. Furthermore, capsaicin prominently reduced the ratio of anti-apoptotic Bcl-2 to pro-apoptotic Bax and consequently increased caspase-3 activity. These results demonstrate that capsaicin efficiently induced apoptosis in SK-Hep-1 cells through a caspase-3-dependent mechanism, which may contribute to its chemopreventive function.
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PMID:Capsaicin-induced apoptosis in SK-Hep-1 hepatocarcinoma cells involves Bcl-2 downregulation and caspase-3 activation. 1127 62

Autonomous parvoviruses preferentially replicate in and kill in vitro-transformed cells and reduce the incidence of spontaneous and implanted tumors in animals. Because of these natural oncotropic and oncolytic properties, parvoviruses deserve to be considered as potential antitumor vectors. Here, we assessed whether parvovirus H1 is able to kill human hepatoma cells by induction of apoptosis but spares primary human liver cells, and whether the former cells can efficiently be transduced by H1 virus-based vectors. Cell death, infectivity, and transgene transduction were investigated in Hep3B, HepG2, and Huh7 cells and in primary human hepatocytes with natural and recombinant H1 virus. All hepatoma cells were susceptible to H1 virus-induced cytolyis. Cell death correlated with H1 virus DNA replication, nonstructural protein expression, and with morphological features of apoptosis. H1 virus-induced apoptosis was more pronounced in p53-deleted Hep3B and p53-mutated Huh7 cells than in HepG2 cells which express wild-type p53. In Hep3B cells, apoptosis was partially inhibited by DEVD-CHO, a caspase-3 inhibitor. In contrast, H1 virus-infected primary hepatocytes were neither positive for nonstructural protein expression nor susceptible to H1 virus-induced killing. Infection with a recombinant parvovirus vector carrying the luciferase gene under control of parvovirus promoter P38 led to higher transgene activities in hepatoma cells than in the hepatocytes. Taken together, H1 virus kills human hepatoma cells at low virus multiplicity but not primary hepatocytes. Thus, recombinant H1 viruses carrying antitumor transgenes may be considered as potential therapeutic options for the treatment of hepatocellular carcinomas.
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PMID:Effective infection, apoptotic cell killing and gene transfer of human hepatoma cells but not primary hepatocytes by parvovirus H1 and derived vectors. 1133 86

We demonstrated the induction of cell death in a hepatoma cell line by IFN-gamma and its possible mechanism. Among the 2 hepatitis B virus (HBV)-associated hepatoma cell lines, SNU-354 and SNU-368, IFN-gamma induced cell death and increased caspase-3 activity in SNU-368 but not in SNU-354. IFN-gamma induced several changes in the mRNA expression level of apoptosis-regulating genes, e.g., increased expression of Fas, caspase-1 and TNF-related apoptosis-inducing ligand (TRAIL). In particular, IFN-gamma potently increased the mRNA expression of TRAIL in both cell lines. However, it did not change the mRNA expression level of death-mediating TRAIL receptors, e.g., DR4 and DR5, which were constitutively expressed in both cell lines. In contrast, the decoy receptor DcR1 was expressed in SNU-354 but not in SNU-368, and its expression level in SNU-354 was increased by IFN-gamma. Another decoy receptor, DcR2, was constitutively expressed in both cell lines; however, its expression level in SNU-368 was decreased by IFN-gamma. In addition, exogenous recombinant TRAIL reduced viability in SNU-368, but not in SNU-354, cells. From these findings, we speculated that TRAIL up-regulation and the subsequent TRAIL-mediated apoptosis serve as a mechanism of IFN-gamma-induced cell death in SNU-368. To confirm this hypothesis, we demonstrated that soluble DR4-Fc fusion protein, a TRAIL pathway inhibitor, inhibited IFN-gamma-induced cell death in SNU-368. Our results demonstrated that IFN-gamma acts as an inducer of cell death through TRAIL-mediated apoptosis.
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PMID:IFN-gamma induces cell death in human hepatoma cells through a TRAIL/death receptor-mediated apoptotic pathway. 1141 Aug 75


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