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)

Glucocorticoids are primarily recognized for their profound anti-inflammatory actions and their ability to induce lymphocyte apoptosis. We report here that, in contrast to their effect on cells of the immune system, glucocorticoids suppress serum deprivation induced apoptosis of rat hepatoma (HTC) cells. Suppression of apoptosis in these cells occurs at physiological concentrations of glucocorticoid and is abrogated by the glucocorticoid antagonist RU486. Although HTC cells also express receptors for progesterone, estrogen, and thyroid hormone, ligands for these receptors fail to rescue these cells from programmed cell death. Because the sensitivity of cells to apoptotic stimuli is often regulated by the ratio of antiapoptotic to proapoptotic Bcl-2 family members, we analyzed the influence of glucocorticoids and induction of apoptosis by serum starvation on the expression of these proteins. Bcl-2, Bcl-xL, Bad, Bak, and Bax levels were not altered by either treatment. Mitochondrial function has recently been implicated as a critical early regulator of apoptosis in many cells including hepatocytes. Dexamethasone treatment blocked a decrease in this potential (delta psi(m)) during serum deprivation induced apoptosis in HTC cells, indicating an action of this hormone upstream of mitochondria. We also show that the induction of apoptosis in HTC cells is associated with a decrease in nuclear factor (NF)-kappaB. Treatment with dexamethasone effectively blocked the loss of nuclear NF-kappaB, suggesting that this hormone acts to suppress apoptosis of HTC cells via regulation of this nuclear transcription factor. This hypothesis was confirmed by transfection experiments that show that expression of a superrepressor of NF-kappaB inhibits the ability of dexamethasone to rescue HTC cells from apoptosis induced by serum deprivation.
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PMID:Delineation of an antiapoptotic action of glucocorticoids in hepatoma cells: the role of nuclear factor-kappaB. 1080 96

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

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

As a mitochondrial membrane death ligand, Bid oligomerises Bak to release cytochrome C and its deficiency renders hepatocytes resistant to apoptosis induced by Fas. The Bid level in hepatocellular carcinoma (HCC) is unknown. In this report, we examined the expression of Bid protein and mRNA in HCC cancerous tissues and their corresponding non-cancerous ones. The effect of the hepatitis B x protein (HBx) on the expression of Bid was also evaluated by transfecting hepatoma cells with the HBx gene. The results showed that the expression of Bid was significantly lower in cancerous tissues than that in their corresponding non-cancerous tissues. Immunohistochemical study revealed that Bid molecule was mainly localised in hepato-cytoplasm. Some nuclei were also positive for Bid antigen though to a lesser degree. In vitro experiments demonstrated that the expression of Bid in cells transfected with HBx was significantly lower than that in the cells without HBx transfection. This finding suggests that HBx may play a causative role in the reduction of Bid expression in HCC. This in vitro result is, to some degree, supported by clinical data that all the HCC examined are positive for hepatitis B virus (HBV). We conclude from this data that the expression of Bid in HCC is significantly decreased and the reduction of Bid may result from a mechanism associated with HBx, a major hepatocarcinogenic product from HBV. The imbalance of increased anti-apoptosis and decreased pro-apoptosis seen in HCC is a critical mechanism leading to the uncontrolled growth of tumour cells. Therefore, this study suggests that a deficiency in the expression of Bid may contribute to the development of such an imbalance in HCC.
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PMID:Decreased expression of Bid in human hepatocellular carcinoma is related to hepatitis B virus X protein. 1152 98

AIM:We have previously reported that inducible over-expression of Bak may prolong cell cycle in G(1) phase and lead to apoptosis in HCC-9204 cells. This study is to investigate whether p27(KIP1) plays an important role in this process.METHODS:In order to elucidate the exact function of p27(KIP1) in this process, a zinc inducible p27(KIP1) stable transfectant and transient p27(KIP1)-GFP fusion transfectant were constructed. The effects of inducible p27(KIP1) on cell growth, cell cycle arrest and apoptosis were examined in the mock, control pMD vector, and pMD-KIP1 transfected HCC-9204 cells.RESULTS:This p27(KIP1)-GFP transfectant may transiently express the fusion gene. The cell growth was reduced by 35% at 48 h of p27(KIP1) induction with zinc treatment as determined by trypan blue exclusion assay. These differences remained the same after 72h of p27(KIP1) expression. p27(KIP1) caused cell cycle arrest after 24 h of induction, with 40% increase in G(1) population. Prolonged p27(KIP1) expression in this cell line induced apoptotic cell death reflected by TUNEL assay. Fourty-eight h and 72 h of p27(KIP1) expression showed a characteristic DNA ladder on agarose gel electrophoresis.CONCLUSION:Bak may induce cell cycle arrest in G(1) phase through upregulating expression of p27(KIP1) and subsequently lead to apoptosis in HCC-9204 cells. The p27(KIP1) -GFP fusion protein can be transiently expre-ssed in HCC-9204 cells. The inducible p27(KIP1)-expressing cell line provides a model to assess p27(KIP1) function.
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PMID:Overexpression of p27(KIP1) induced cell cycle arrest in G(1) phase and subsequent apoptosis in HCC-9204 cell line. 1181 39

Herbal medicines are increasingly being utilized to treat a wide variety of disease processes. Gypenosides (Gyp) are triterpenoid saponins contained in an extract from Gynostemma pentaphyllum Makino and reported to induce apoptosis in human hepatoma cells. However, the molecular mechanism underlying the Gyp-induced apoptotic process is unclear. In this study, we found that Gyp induced apoptosis in human hepatoma Huh-7, Hep3B and HA22T cell lines as evidenced by morphological changes, 4',6'-diamidino-2-phenylindole staining and in situ terminal transferase-mediated dUTP-fluorescensin nick end-labeling assay. Our data demonstrated that Gyp-induced apoptotic cell death was accompanied by up-regulation of Bax, Bak and Bcl-X(L), and down-regulation of Bcl-2 and Bad, while it had no effect on the level of Bag-1 protein. Moreover, Gyp treatment caused the release of mitochondrial cytochrome c to cytosol and sequential activation of caspases, including caspase-1, -9 and -3, then leading to cleavage of poly-ADP-ribose polymerase. Furthermore, the Gyp-induced apoptosis was markedly blocked by the broad-spectrum caspase inhibitor, z-VAD-fmk. Taken together, these results suggest that treatment of human hepatoma cells with Gyp induced apoptosis through the up-regulation of Bax and Bak, and down-regulation of Bcl-2, release of mitochondrial cytochrome c and activation of caspase cascade.
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PMID:Regulation of Bcl-2 family molecules and activation of caspase cascade involved in gypenosides-induced apoptosis in human hepatoma cells. 1206 92

Since hepatocellular carcinoma remains a major challenging clinical problem in many parts of the world including Eastern Asia and Southern Africa, it is imperative to develop more effective chemopreventive and chemotherapy agents. Herein, we present an investigation regarding the anticancer potential of luteolin, a natural flavonoid, and the mechanism of its action in human hepatoma HepG2 cells. Using DNA fragmentation assay and nuclear staining assay, it showed that luteolin induced apoptosis of HepG2 cells. Luteolin induced the cytosolic release of cytochrome c and activated CPP32. We found that Bax and Bak translocated to mitochondria apparently, whereas Fas ligand (FasL) was unchanged after a treatment with luteolin for 3 h. In addition, it showed that c-Jun NH2-terminal kinase (JNK) was activated after the treatment of luteolin for 3-12 h. Further investigation showed that a specific JNK inhibitor, SP600125, reduced the activation of CPP 32, the mitochondrial translocation of Bax, as well as the cytosolic release of cytochrome c that induced by luteolin. Finally, the apoptosis induced by luteolin was suppressed by a pretreatment with SP600125 via evaluating annexin V-FITC binding assay. These data suggest that luteolin induced apoptosis via mechanisms involving mitochondria translocation of Bax/Bak and activation of JNK.
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PMID:Induction apoptosis of luteolin in human hepatoma HepG2 cells involving mitochondria translocation of Bax/Bak and activation of JNK. 1571 Jan 73

Glycyrrhetinic acid (GA) and its related compounds are known to have anti-inflammatory activity and also to inhibit liver carcinogenesis and tumor growth. GA and related compounds inhibited cell proliferation of the human hepatoma cell line, HepG2. Among five compounds tested, ursolic acid and 18beta-olean-12-ene-3beta, 23, 28-triol (18beta-erythrotriol) were comparatively effective, where the 50% inhibitory dose was 20 microM and 25 microM, respectively. Flow-cytometric analysis showed that GA and the related compounds arrested the cell cycle in the G1-phase; in addition, GA-related compounds induced apoptosis at high dose. Western blot analysis indicated that the induction of apoptosis by GA and ursolic acid was accompanied with an activation of caspase-8 and a reduction in the anti-apoptotic proteins, Bcl-2 and Bcl-xL, although the pro-apoptotic proteins, Bax and Bak, remained unaffected. These results suggest that GA and its related compounds may be potent agents in liver cancer treatment.
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PMID:Glycyrrhetinic acid and related compounds induce G1 arrest and apoptosis in human hepatocellular carcinoma HepG2. 1630 97

Justicia procumbens is a traditional Taiwanese herbal remedy used to treat fever, pain, and cancer. Justicidin A, isolated from Justicia procumbens, has been reported to suppress in vitro growth of several tumor cell lines as well as hepatoma cells. In this study, justicidin A activated caspase-8 to increase tBid, disrupted mitochondrial membrane potential (Delta psi(m)), and caused the release of cytochrome c and Smac/DIABLO in Hep 3B and Hep G2 cells. Justicidin A also reduced Bcl-x(L) and increased Bax and Bak in mitochondria. Caspase-8 inhibitor (Z-IETD) attenuated the justicidin A-induced disruption of Delta psi(m). Growth of Hep 3B implanted in NOD-SCID mice was suppressed significantly by oral justicidin A (20 mg/kg/day). These results indicate that justicidin A-induced apoptosis in these cells proceeds via caspase-8 and is followed by mitochondrial disruption.
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PMID:Caspase-8 acts as a key upstream executor of mitochondria during justicidin A-induced apoptosis in human hepatoma cells. 1668 33

The constitutive androstane receptor (CAR) modulates xeno- and endobiotic hepatotoxicity by regulating detoxification pathways. Whether activation of CAR may also protect against liver injury by directly blocking apoptosis is unknown. To address this question, CAR wild-type (CAR+/+) and CAR knockout (CAR-/-) mice were treated with the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and then with the Fas agonist Jo2 or with concanavalin A (ConA). Following the administration of Jo2, hepatocyte apoptosis, liver injury, and animal fatalities were abated in TCPOBOP-treated CAR+/+ but not in CAR-/- mice. Likewise, acute and chronic ConA-mediated liver injury and fibrosis were also reduced in wild-type versus CAR(-/-) TCPOBOP-treated mice. The proapoptotic proteins Bak (Bcl-2 antagonistic killer) and Bax (Bcl-2-associated X protein) were depleted in livers from TCPOBOP-treated CAR+/+ mice. In contrast, mRNA expression of the antiapoptotic effector myeloid cell leukemia factor-1 (Mcl-1) was increased fourfold. Mcl-1 promoter activity was increased by transfection with CAR and administration of TCPOBOP in hepatoma cells, consistent with a direct CAR effect on Mcl-1 transcription. Indeed, site-directed mutagenesis of a putative CAR consensus binding sequence on the Mcl-1 promoter decreased Mcl-1 promoter activity. Mcl-1 transgenic animals demonstrated little to no acute liver injury after administration of Jo2, signifying Mcl-1 cytoprotection. In conclusion, these observations support a prominent role for CAR cytoprotection against Fas-mediated hepatocyte injury via a mechanism involving upregulation of Mcl-1 and, likely, downregulation of Bax and Bak.
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PMID:Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins. 1679 68


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