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)

The ability of ricin, a type II ribosome-inactivating protein, to induce hepatoma cell (BEL7404) to apoptosis in vitro was examined by fluorescence microscopy, flow cytometry, and DNA fragmentation assay. As a Bcl-2 lacking model, BEL7404 bore unique advantage to study the effect of over-expressing Bcl-2 on the apoptosis induced by the inhibitor of protein synthesis. By establishing a Bcl-2 over-expressing cell line (BEL7404/ Bcl-2), we found that Bcl-2 could promote the survival of the hepatoma cell against ricin insult. The ricin-induced apoptosis of BEL7404 was accompanied by increased expression of Bak and decreased levels of Bcl-xl and Bax. Caspases and PARP cleavage activity were found to be implicated in the death process. Through the inhibitor tests, our results excluded the participation of calcium-dependent proteases or protein kinase C in the apoptotic process induced by ricin, though an elevation of intracellular calcium did occur as an immediate response to ricin treatment. Cycloheximide, another protein synthesis inhibitor, did synergistically enhance rather than inhibit the cytotoxicity of ricin to hepatoma cell BEL7404. Actually, cycloheximide alone was able to induce hepatoma cell BEL7404 to death that could also be inhibited by over-expressing Bcl-2. The elevation of apoptotic protein Bak was discussed to challenge the notion that ricin exerted its cytotoxicity through nonspecific inhibition of all the de novo protein synthesis.
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PMID:An insight into the mechanism of cytotoxicity of ricin to hepatoma cell: roles of Bcl-2 family proteins, caspases, Ca(2+)-dependent proteases and protein kinase C. 1132 13

An immortal human hepatic cell line HL-7702 and human hepatoma cell line SMMC-7721 were treated with 3-30 microM SeO(2). SeO(2) at 30 microM markedly inhibited cell proliferation and viability, and prompted apoptosis of both normal hepatic and hepatoma cells after 48h treatment. SeO(2) could also down-regulate the Bcl-2 level, greatly in HL-7702 and slightly in SMMC-7721 cells, but up-regulate wild type P53 level a little in HL-7702 and significantly in SMMC-7721 cells. The Bcl-2/P53 value was closely correlated with the apoptotic rate as well as SeO(2) concentrations.
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PMID:SeO(2) induces apoptosis with down-regulation of Bcl-2 and up-regulation of P53 expression in both immortal human hepatic cell line and hepatoma cell line. 1134 37

Bcl-2 family proteins play a critical role in the regulation of apoptosis. Treatment of a human hepatocellular carcinoma cell line, QGY-7703, with Taxol induced apoptosis and Bcl-2 protein phosphorylation. Microscopic observation indicated that apoptotic bodies (0-15%) of Taxol-treated QGY cells appeared after 12 h of treatment, and apoptotic QGY cells gradually increased to 40% after 24 h and 70% after 48 h. A DNA fragmentation assay showed that Taxol induced genomic DNA cleavage into 200 bp DNA fragments. Bcl-2 protein was phosphorylated in Taxol-treated QGY cells within 3 h of treatment, and continued gradually up to 24 h. By 48 h, the protein was unphosphorylated. Other Bcl-2 family proteins, including Bax (a heterodimerization partner of Bcl-2), Bcl-XL, Bak and Bad, were expressed, but at constant levels. The results show a close correlation between Bcl-2 phosphorylation and apoptosis in QGY cells. The inactivation of Bcl-2 protein phosphorylation could be one of the key mechanisms needed for the induction of apoptosis in Taxol-treated QGY cells.
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PMID:Taxol induced Bcl-2 protein phosphorylation in human hepatocellular carcinoma QGY-7703 cell line. 1135

c-Myc has been documented to be both a positive and a negative signal for the induction of apoptosis. It is well known that overexpression of the c-myc gene induces apoptosis of normal cells, but the result of a reduction in its expression is not fully understood. We examined whether a reduction in c-myc expression would induce apoptosis in human liver cancer cells. Specifically, antisense and sense oligodeoxynucleotides (oligos) against the human c-myc mRNA were synthesized, mixed with a liposome reagent at various ratios, and were applied to the liver cancer-derived cell lines, HCC-T, HepG2, and PLC/PRF/5. To exclude effects resulting from using oligos, plasmid vectors expressing the full-length c-myc cDNA in both sense and antisense orientations under the control of the Cre/loxP system were generated. Monoclonal cell lines including these plasmid vectors were produced and Cre was supplied by adenovirus infection. Apoptosis was determined morphologically and c-Myc and Bcl-2 expression was examined by Western blotting. The antisense myc significantly inhibited the proliferation of the cells within two days, while neither the liposome reagent alone nor sense myc did so. Most of the cells were rounded up by the antisense-treatment and nuclear fragmentation and DNA ladder formation were detected after two days in antisense c-myc-treated cells. Antisense c-myc largely reduced c-Myc and partially Bcl-2 expression; overexpression of Bcl-2 partially rescued from apoptosis in HCC-T and HepG2 cells. These results suggest that the massive reduction in c-myc mRNA induces apoptosis in liver cancer cell lines and consequent decrease in Bcl-2 enhances the cell death. c-Myc reduction under the Cre/loxP switching system may be a useful tool for the clarification of c-myc-related cellular mechanisms in differentiation and proliferation.
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PMID:Reduction of c-myc expression by an antisense approach under Cre/loxP switching induces apoptosis in human liver cancer cells. 1138 22

Transformed hepatocytes survive various apoptotic insults during their growth in vivo. However, molecular mechanisms that inhibit apoptosis and support their survival are not well understood. In this study, we investigated the expression and role of Bcl-xL, an antiapoptotic member of the Bcl-2 family, in human hepatocellular carcinoma (HCC). The Bcl-xL protein was expressed in HepG2, Hep3B, and Huh7 human hepatoma cell lines at high levels, but none of these cells expressed Bcl-2. Down-modulation of Bcl-xL by antisense oligonucleotide activated apoptosis in HepG2 cells in response to cellular stresses induced by staurosporine treatment or by serum starvation. Ectopic expression of transcriptionally active p53 alone was not sufficient for the activation of apoptosis in p53-null Hep3B cells, but apoptosis was induced when endogenous Bcl-xL was simultaneously inhibited by antisense oligonucleotide in these cells. Bcl-xL was expressed in all 20 surgically resected human HCC tissues when examined by Western blot analysis and immunohistochemistry, and levels of its expression were higher in a subset of HCC tissues than those of adjacent nontumor liver tissues or normal livers. We conclude that Bcl-xL expressed in human HCC cells inhibits apoptosis produced by various cellular stresses, such as staurosporine treatment, serum starvation, and p53 activation, and may play an important role in their survival.
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PMID:Expression and role of Bcl-xL in human hepatocellular carcinomas. 1143 34

Pancreatic cancer cells are usually resistant to apoptosis mediated by intrinsic or extrinsic factors. BAG-3 (Bis, CAIR), which was identified as a BAG-1-related protein, is a novel modulator of cellular anti-apoptotic activity that functions through its interaction with Bcl-2. In this study we analyzed BAG-3 expression in human pancreatic cancer tissues and cell lines. BAG-3 mRNA was expressed at moderate to high levels in all pancreatic cancer samples, but at low levels in normal pancreas tissues. In situ hybridization and immunohistochemistry analysis revealed that BAG-3 was present in the cancer cells within the pancreatic tumor mass. When BAG-3 mRNA was analyzed in other gastrointestinal cancers (hepatocellular carcinoma; esophageal, stomach and colon cancer), no difference was found from their corresponding normal controls. In pancreatic cancer cells, BAG-3 mRNA expression levels were strongly induced after heat stress, but not in response to members of the tumor necrosis factor (TNF)-alpha family (TNF-alpha, TRAIL, FasL). These findings indicate that in pancreatic cancer, in contrast to other gastrointestinal malignancies, increased levels of BAG-3 might function to block apoptosis. This characteristic of pancreatic cancer might contribute to its more aggressive growth behavior and poor responsiveness to treatment in vivo.
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PMID:The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines. 1151 73

Geranylgeraniol (GGOH), an intermediate of mevalonate metabolism, is known to induce apoptosis in various lines of cancer cells. The present study was undertaken to clarify the signaling pathways of apoptosis induced by GGOH in human hepatoma cells. HuH-7 human hepatoma cells were incubated in the absence or presence of GGOH. Activation of caspase-8 /-9 /-3 in HuH-7 cells was found after 8 h treatment with GGOH, at which time DNA fragmentation and loss of mitochondrial transmembrane potential (Deltaphim) occurred. HuH-7 cells do not express Bcl-2; however, down-regulation of Bcl-xL expression preceded activation of the caspase cascade in GGOH-treated HuH-7 cells, while Bax expression was not changed by GGOH treatment. Addition of caspase inhibitors restored the decreased cell viability of HuH-7 cells by GGOH, including Deltaphim, to the baseline level, which indicated that caspase triggers mitochondria-dependent apoptotic pathways in GGOH-treated HuH-7 cells. Similarly, GGOH-mediated apoptosis of HuH-7 cells was clearly prevented by coadministration of ursodeoxycholic acid (UDCA), which led to restoration of the level of Bcl-xL expression. Activation of caspase-8 /-9 /-3, as well as Deltaphim, by GGOH treatment was suppressed by addition of UDCA. Our results indicate that activation of the caspase cascade initiating from caspase-8, which could be accelerated by down-regulation of Bcl-xL expression, plays a key role in an apoptotic process induced by GGOH in human hepatoma cells.
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PMID:Geranylgeraniol, an intermediate product in mevalonate pathway, induces apoptotic cell death in human hepatoma cells: death receptor-independent activation of caspase-8 with down-regulation of Bcl-xL expression. 1157 58

Bid, a member of the Bcl-2 family, mediates apoptosis by inducing the release of proapoptotic factors. The expression of Bid in liver diseases has not been investigated. This study evaluated Bid level in various liver diseases including hepatocellular carcinoma (HCC), liver metastases from colorectal cancer, chronic hepatitis and liver cirrhosis. The expression of Bid in tumorous tissues of HCC was lower than that in their corresponding non-tumorous tissues from the same patient. Heavy staining with Bid antibody was found in some localized tumorous liver tissues from patients with poorly differentiated tumors. In patients with chronic hepatitis and liver cirrhosis, there were gradient tumor-development centers, a gradient increase in reaction with Bid antibody from the middle of the center to its edge. The gradient tumor-development center was also found in non-tumorous tissues of HCC, suggesting that occurrence of this center in chronic hepatitis might be an early pathologic sign of HCC development. Bid was also expressed in the epithelial cells in tissues from liver metastases and their expression was often stronger than in the non-tumorous liver tissues. Heavy nuclear staining of Bid was not uncommon in these metastatic cells. The different patterns of staining between primary and secondary liver tumors may reflect a difference in tumor origin and in cell type. Nuclei of metastatic cells, though positive for Bid, still showed a considerable mitotic activity, indicating that they were in active proliferation rather than on a pathway deemed to be apoptotic. In conclusion, this study shows that the Bid level is decreased in HCC except in poorly differentiated HCC in which cells may undergo a process of apoptosis or necrosis. The existence of gradient tumor-development center in chronic hepatitis, liver cirrhosis and non-tumorous tissues from HCC may serve as a pathologic marker of a carcinogenic change of cell phenotypes.
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PMID:Immunohistochemical analysis of pro-apoptotic Bid level in chronic hepatitis, hepatocellular carcinoma and liver metastases. 1159 32

Dietary organosulphur compounds including diallylsulphide, a component of garlic oil, were shown to inhibit the proliferation of tumour cells. Since hepatocellular carcinoma is one of the most lethal malignancies and there is no effective preventive measure to date, we wished to pursue the chemopreventive potential of the synthetic allylthiopyridazine derivatives (K compounds) on hepatocarcinoma cells. Here, we report that the K compounds efficiently inhibited SK-Hep-1 cell proliferation through induction of apoptosis. Increased chain length at the 3-position of allylthiopyridazine ring improved the potency of growth inhibition. K compounds downregulated Bcl-2, while Bax remained unchanged, reducing the ratio of Bcl-2 to Bax. We also provide evidence that the K compound-induced apoptosis involves cytochrome c release and caspase-3 activation. These results suggest that the allythiopyridazine derivatives, especially 3-propoxy-6-allylthiopyridazine, induce apoptosis in SK-Hep-1 cells through a caspase-3-dependent mechanism, which may contribute to the chemopreventive function for hepatocellular carcinoma.
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PMID:Chemopreventive allylthiopyridazine derivatives induce apoptosis in SK-Hep-1 hepatocarcinoma cells through a caspase-3-dependent mechanism. 1159 91

Tumour necrosis factor alpha (TNF-alpha) at 20 ng/ml induced apoptosis in human hepatoma cells in vitro. The effect of TNF-alpha-induced apoptosis was exacerbated by the hypoxanthine-xanthine oxidase (HX/XO) system and cycloheximide (CHX), but alleviated by superoxide dismutase (SOD), suggesting that TNF-alpha-induced apoptosis may be due to oxidative stress, and independent of protein synthesis. TNF-alpha elevated free Ca(2+)concentration, triggered lipid peroxidation and decreased the expression of bcl-2 protein. The findings suggest that TNF-alpha-induced apoptosis may be involved in stimulating Ca(2+)-dependent endonuclease activity and increasing membrane lipid peroxidation. Bcl-2 may play a pivotal role in serving as a Ca(2+)regulator or antioxidant, preventing lipid peroxidation in the process.
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PMID:Mechanisms of the induction of apoptosis in human hepatoma cells by tumour necrosis factor-alpha. 1174 14


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