Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Direct exposure of human hepatoma cell line SMMC-7721 to hydrogen peroxide (H2O2) can induce apoptosis. Apoptosis induced by H2O2 was inhibited by cycloheximide, actinomycin D, 3-aminobenzamide, EGTA or Zn2+. H2O2 can increase the level of intracellular Ca2+, downregulate GSH levels, slightly induce lipid peroxidation, and lead to change in the ratio of reduced ion components to oxidized ion components of cells. Analysis of flow cytometry indicates that H2O2 decreases the level of Bcl-2. The data indicate that H2O2-induced apoptosis requires new mRNA and protein syntheses; H2O2 can activate Ca2+/Mg2+-dependent endonuclease leading to internucleosomal DNA fragmentation and activation of poly (ADP-ribose) polymerase interfering with the energy metabolism of the cell. The H2O2 downregulation of GSH may be more important for apoptosis than H2O2 induction of lipid peroxidation, and the H2O2 induced changes in redox status of the cell may be among the original events which lead up to other biochemical changes.
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PMID:Hydrogen peroxide induces apoptosis in human hepatoma cells and alters cell redox status. 1082 69

Hepatitis C virus (HCV) infection is associated with the development of hepatocellular carcinoma. Several lines of evidence suggest that the core protein of HCV may play a role in the development of this cancer. The authors examined regulation of the cell cycle in stable cell lines derived from Chinese hamster ovary (CHO-K1) cells that constitutively expressed one or more of the structural proteins of HCV. In media containing low concentrations of serum (serum starvation), cell lines expressing the core protein showed a significantly lower population of viable cells than noncore-expressing cells. The low viability of the core-expressing cells was a result of the increased population of cells undergoing apoptosis. Interestingly, the cell cycle analysis revealed that the arresting function at G(0) was impaired, and the cell cycle was accelerated in core-expressing cell lines even under serum starvation. Thus, the HCV core protein sensitizes the apoptosis to serum starvation, although it promotes the cell cycle in CHO-K1 cells. To explain these findings, the authors examined the expression of revival apoptosis and cell-cycle-related genes. Expression of the c-myc genes was significantly induced in core-expressing cells in response to serum starvation. Other apoptosis-inducing genes downstream of c-myc, p53, p21WAF1/CIP1 and Bax were significantly highly induced, although there was no induction of Bcl-2, which prevents apoptosis in core-expressing cells. Thus, the HCV core protein induced apoptosis and impaired the regulation of the cell cycle by activating c-myc expression, whereas the p53 and Bax pathways play a role in the induction of apoptosis.
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PMID:Hepatitis C virus core protein induces apoptosis and impairs cell-cycle regulation in stably transformed Chinese hamster ovary cells. 1082 63

As the occurrence of structural p53 mutations in hepatocellular carcinoma (HCC) in Thailand was previously reported to be much lower than that found in other high-incidence HCC areas, we analyzed 16 HCC samples from Thailand to determine the expression and functionality of p53 protein. We observed the overexpression of p53 protein in 69% of HCC, despite the prevalence of the wild-type p53 gene. However, the overexpressed p53 protein was nonfunctional as suggested by its inability to modulate the expressions of several p53 effector proteins (p21 and Bcl-2 family proteins). In addition, we observed significant underexpression of two proapoptotic proteins, Bax and Bcl-X(S), in 81% (P = 0.02) and 64% (P = 0.03) of HCC, respectively. Consequently, the ratios of proapoptotic to antiapoptotic BCL-2 family proteins were reduced in 88% of the HCC tumor tissues when compared to normal tissues, such that the rheostat between BCL-2 family proteins is strongly skewed toward enhanced cell survival in the tumor cells.
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PMID:Downregulation of proapoptotic proteins Bax and Bcl-X(S) in p53 overexpressing hepatocellular carcinomas. 1087 63

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

Apoptosis plays an important role in embryonic development, tissue remodeling, immune regulation and tumor regression. Two groups of molecules (Bcl-2 family and "Death factor" family) are involved in regulating apoptosis. In order to know about the effect of Bcl-2 on apoptosis induced by Fas, a typical member of "Death factor" family, the transfection experiments with expression vectors pcDNA3-fl and pcDNA3-bcl-2 were performed in BEL-7404 cells, a human hepatocellular carcinoma cell line which expresses endogenous Fas, but not FasL and Bcl-2. The data showed that the expression of FasL in pcDNA3-fl transfected hepatoma cells obviously induced the apoptosis of the cells. However, the overexpression of Bcl-2 in pcDNA3-bcl-2 transfected 7404/b-16 cells counteracted pcDNA3-fl transient transfection mediated apoptosis. Further study by co-transfection experiments indicated that Bid but not Bax (both were pro-apoptotic proteins of Bcl-2 family) blocked the inhibitory effect of Bcl-2 on Fas-mediated apoptosis. These results suggested that Fas-mediated apoptosis in human hepatoma cells is possibly regulated by Bcl-2 family proteins via mitochondria pathway.
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PMID:Expression of Bcl-2 inhibited Fas-mediated apoptosis in human hepatocellular carcinoma BEL-7404 cells. 1103 75

In order to understand how cancer cells accumulate, rat hepatoma ARL-6 cells were cultured for 8 d to identify factors involved in spontaneous cell proliferation and apoptosis. With increasing time in culture, the proportion of cells in the proliferative phases of the cell cycle and the rate of deoxyribonucleic acid (DNA) synthesis decreased. The waning of proliferation was associated with a gradual reduction of cell viability, and this was temporally related to the appearance of typical apoptotic morphology and DNA laddering. Medium replacement or supplementation with fetal calf serum (FCS) suppressed apoptosis, while medium change, but not fetal calf serum alone, enhanced cell proliferation. Apoptosis was also suppressed by dimethyl sulfoxide (DMSO), but supplementary glutathione was without effect. Expression of poly(adenosine diphosphate[ADP]-ribose)polymerase peaked on days 34 of culture, and was followed by a progressive decrease thereafter, consistent with proteolytic cleavage. This decrease was prevented to varying extents by complete medium replacement, FCS and DMSO, indicating a close temporal relationship between poly(ADP-ribose)polymerase activation and apoptosis. Expression of Fas and Bcl-2 did not change appreciably over the 8-d culture, but there was a gradual increase in Bax expression; medium change, FCS and DMSO all partly inhibited Bax expression. These data indicate that spontaneous apoptosis in cultured ARL-6 cells is inversely related to cell proliferation, and that nutrient supply, and to a lesser extent, serum-derived factors and oxidative stress modulate apoptosis in this system. Proteolytic cleavage of poly(ADP-ribose)polymerase and expression of Bax are likely to be mechanistically involved with the control of spontaneous apoptosis in ARL-6 cells, whereas changes in the levels of Fas and Bcl-2 do not play a role.
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PMID:Reciprocal control of apoptosis and proliferation in cultured rat hepatoma arl-6 cells: roles of nutrient supply, serum, and oxidative stress. 1103 96

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

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

Aldehyde dehydrogenases (ALDHs) are a family of several isoenzymes expressed in various tissues and in all subcellular fractions. In some tumours, there is an increase of ALDH activity, especially that of class 1 and 3. The increase in the activity of these isoenzymes is correlated with cell growth and drug resistance shown by these cells. It has been observed that hepatoma cells expressing low ALDH3 activity are more susceptible to growth inhibition by low concentration of lipid peroxidation products than hepatoma cells expressing high ALDH3 activity. The products of lipid peroxidation are good substrates for ALDH, but when their intracellular levels are increased in hepatoma cells treated repeatedly with prooxidants, they inhibit ALDH3 and bring about growth inhibition or cell death. As a follow up to the work previously reported on S-methyl 4-amino-4-methylpent-2-ynethioate, a synthetic suicide inhibitor of ALDH1, which induced bcl2 overexpressing cells into apoptosis and exhibited an ED50 of 400 microM, a novel broad spectrum inhibitor of ALDH1 and ALDH3 was synthesised. This new compound (ATEM) is a suicide inhibitor of ALDH1, an irreversible inhibitor of ALDH3 and exhibits an ED50 of 10-25 microM on rat cultured hepatoma cells. Four hours after treatment with 25 microM ATEM, ALDH activity using benzaldehyde or propionaldehyde in hepatoma cells was decreased by 40% and cell number by 15% compared with controls. As cell growth did not resume when the inhibitor was removed from the culture medium, it suggested strongly that ALDHs play a pivotal role in mediating cell death.
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PMID:The effect of a novel irreversible inhibitor of aldehyde dehydrogenases 1 and 3 on tumour cell growth and death. 1130 45

Intravenous administration of tumor necrosis factor-alpha (TNF-alpha) (0.5 microg/mouse) caused hepatocyte apoptosis in BALB/c mice when they were sensitized with D-galactosamine (GalN, 20 mg/mouse). Activation of nuclear factor kappa B (NF-kappa B) and expression of apoptotic Bcl-2 family members were not significantly different between livers of mice treated with TNF-alpha alone and GalN + TNF-alpha, indicating that neither activation of NF-kappa B nor expression of Bcl-2 family is involved in the sensitization by GalN against TNF-alpha-induced hepatocyte apoptosis. To identify differentially expressed genes implicated in GalN-induced hepatocyte sensitization, we adopted mRNA fingerprinting using an arbitrarily primed polymerase chain reaction. The present analysis revealed that mRNA expression of extracellular antioxidant, selenoprotein P, was up-regulated in the livers after GalN administration. GalN-induced increase in its protein level was confirmed by Western blotting. Increased expression of this gene was also observed in the liver of mice treated with concanavalin A, but not anti-Fas antibody. mRNA of another antioxidant, glutathione peroxidase-1, was also up-regulated, and lipid peroxides were produced in the liver after GalN administration. Selenoprotein P mRNA level also increased in Huh-7 human hepatoma cells incubated with GalN (5 or 10 mM). Accordingly, formation of reactive oxygen species (ROS) was observed in GalN-treated Huh-7 cells. H(2)O(2) induced up-regulation of selenoprotein P mRNA and sensitized Huh-7 cells to TNF-alpha-induced apoptosis. These results suggest that ROS produced by GalN may play a pivotal role in hepatocyte sensitization toward TNF-alpha-induced apoptosis.
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PMID:Possible involvement of reactive oxygen species in D-galactosamine-induced sensitization against tumor necrosis factor-alpha-induced hepatocyte apoptosis. 1131 61


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