Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S100 proteins, a subgroup of the EF-hand Ca2+-binding protein family, regulate a variety of cellular processes via interaction with different target proteins. Several pathological disorders, including cancer, are linked to altered Ca2+ homeostasis and might involve the multifunctional S100 proteins, which are expressed in a cell- and tissue-specific manner. The present work demonstrates a distinct intracellular localization of S100A6, S100A4, and S100A2 in two tumor cell lines derived from metastatic epithelial breast adenocarcinoma (MDA-MB231) and cervical carcinoma (HeLa). Treatment of the cells by thapsigargin, the ionophore A23187, or cyclic ADP-ribose, to increase [Ca2+]i via different pathways, led to relocation of S100A6 and S100A4 but only partially of the nuclear S100A2, as demonstrated by confocal laser scanning microscopy. These findings support the hypothesis that S100 proteins could play a crucial role in the regulation of Ca2+ homeostasis in cancer cells.
...
PMID:Subcellular distribution of S100 proteins in tumor cells and their relocation in response to calcium activation. 1042 67

Butyrate exerts potent anti-tumor effects by inhibiting cancer cell growth and inducing apoptosis. However, the molecular mechanisms mediating these effects remain largely unknown. Using the Caco-2 cell line, a well established model of colon cancer cells, our data show that butyrate induced apoptosis (maximum 79%) is mediated via activation of the caspase-cascade. A key event was the proteolytic activation of caspase-3, triggering degradation of poly-(ADP-ribose) polymerase (PARP). Inactivation of caspase-3 with the tetrapeptide zDEVD-FMK completely inhibited the apoptotic response to butyrate. In parallel, butyrate potently up-regulated the expression of the pro-apoptotic protein bak, without changing Caco-2 cell bcl-2 expression. Butyrate-induced Caco-2 cell apoptosis was completely blocked by the addition of cycloheximide, indicating the necessity of protein synthesis. However, when this inhibitor was added at a time point where bak expression was already enhanced (12 - 16 h after butyrate stimulation), it failed to protect Caco-2 cells against apoptosis. Taken together, these data provide evidence that the molecular events involved in butyrate induced colon cancer cell apoptosis include the caspase-cascade and the mitochondrial bcl-pathway.
...
PMID:Butyrate mediates Caco-2 cell apoptosis via up-regulation of pro-apoptotic BAK and inducing caspase-3 mediated cleavage of poly-(ADP-ribose) polymerase (PARP). 1046 46

The oncoprotein MDM2 binds and inactivates p53. MDM2 also binds to the tumor suppressor pRB, as well as E2F-1. E2F-1 is a transcription factor that regulates S phase entry and has been shown to cause apoptosis in some cell types when overexpressed. To investigate the effect of adenovirus-mediated E2F-1 overexpression, MDM2-overexpressing tumor cell lines were treated by mock infection, infection with an adenoviral vector expressing beta galactosidase, or E2F-1 (Ad5CMV-E2F-1). Western blot analysis confirmed significant overexpression of E2F-1 in Ad5CMV-E2F-1-infected cells. E2F-1 overexpression resulted in marked growth inhibition and rapid loss of cell viability. Ad5CMV-E2F-1 infection resulted in early S phase entry, followed by apoptotic cell death. E2F-1 overexpression was associated with a marked decrease in MDM2 levels and no evidence of increased Bax levels, whereas p53 and Bcl-2 levels remained undetectable. Cleavage of poly-ADP-ribose polymerase and caspase 3/CPP32 implicated activation of the caspase cascade in E2F-1-mediated apoptosis. These results indicate that adenovirus-mediated E2F-1 overexpression in MDM2-overexpressing tumor cells results in decreased MDM2 expression and widespread apoptosis. Because MDM2-overexpressing tumors are often resistant to p53 gene therapy, adenovirus-mediated E2F-1 gene therapy may be a promising alternative strategy.
...
PMID:Adenovirus-mediated E2F-1 gene transfer inhibits MDM2 expression and efficiently induces apoptosis in MDM2-overexpressing tumor cells. 1047 12

This study deals with the apoptotic effect exerted on human retinoblastoma Y79 cells by both sodium butyrate and an inhibitor of 26S proteasome [z-Leu-Leu-Leu-CHO (MG132)] and their synergistic effect. Exposure to sodium butyrate (1-4 mM) induced an accumulation of cells in the G2-M phase that was already visible after 24 h of treatment, when morphological and biochemical signs of apoptosis appeared only in a small number of cells (5-10%). Thereafter, the apoptotic effects increased progressively with slow kinetics, reaching a maximum after 72 h of exposure, when they concerned a large fraction of cells (>75% with 4 mM sodium butyrate). Sodium butyrate stimulated the conversion of procaspase-3 into caspase-3 and also induced the cleavage of poly-(ADP-ribose) polymerase and lamin B, two hallmarks of apoptosis. All of the apoptotic signals were suppressed by benzyloxy carbonyl-Val-Ala-Asp-fluoromethylketone (a general inhibitor of caspase activities), whereas acetyl-Asp-Glu-Val-Asp aldehyde, a specific inhibitor of caspase-3 activity, only induced a partial reversion of the apoptotic effects. Sodium butyrate also decreased the Bcl-2 level, whereas it increased the Bax level and stimulated the release of cytochrome c from the mitochondria, an event that was most likely responsible for the activation of caspase-3. Finally, sodium butyrate activated 26S proteasome, the major extralysosomal degradative machinery, which is responsible for the degradation of short-lived proteins. Consequently, the levels of p53, N-myc, and IkappaBalpha (factors that play regulatory roles in apoptosis) diminished, whereas the nuclear level of nuclear factor kappaB concomitantly increased. Treatment of Y79 cells with MG132 induced apoptosis with more rapid kinetics than with sodium butyrate. The effects appeared after 8 h of incubation, reaching a maximum at 24 h, and they were accompanied by increased levels of N-myc, p53, and IkappaBalpha. MG132 also favored the release of cytochrome c from the mitochondria and increased the activity of caspase-3. When Y79 cells were exposed to combinations of sodium butyrate and MG132, the latter compound suppressed the decreasing effect induced by sodium butyrate on the levels of p53, N-myc, and IkappaBalpha and the increasing effect on the nuclear level of nuclear factor kappaB. Moreover, an increase in the level of Bax and an enhancement in the release of cytochrome c from the mitochondria were observed. Clear synergistic effects concerning the activation of both caspase-3 and apoptosis were induced by a combination of suboptimal doses of sodium butyrate and MG132. The results support the conclusion that MG132 potentiates the apoptotic effect of sodium butyrate by suppressing its stimulatory effect on 26S proteasome activity. Synergistic interactions between butyrate and inhibitors of proteasome could represent a new important tool in tumor therapy and, in particular, the treatment of retinoblastoma.
...
PMID:The apoptotic effects and synergistic interaction of sodium butyrate and MG132 in human retinoblastoma Y79 cells. 1055 39

Penta-O-galloyl-beta-D-glucose is structurally related to (-)-epigallocatechin gallate and is isolated from hydrolyzed tannin. Penta-O-galloyl-beta-D-glucose can inhibit tumor promotion by teleocidin. We investigated the effects of penta-O-galloyl-beta-D-glucose and various tea polyphenols on cell viability in human leukemia HL-60 cells. In this study, we demonstrated that penta-O-galloyl-beta-D-glucose was able to induce apoptosis in a concentration- and time-dependent manner; however, other polyphenols were less effective. We further investigated the molecular mechanisms of penta-O-galloyl-beta-D-glucose-induced apoptosis. Treatment with penta-O-galloyl-beta-D-glucose caused induction of caspase-3/CPP32 activity in dose- and time-dependent manner, but not caspase-1 activity, and induced the degradation of poly-(ADP-ribose) polymerase. Pretreatment with acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO) and Z-Val-Ala-Asp-fluoromethyl-ketone (Z-VAD-FMK) inhibited penta-O-galloyl-beta-D-glucose-induced DNA fragmentation. Furthermore, treatment with penta-O-galloyl-beta-D-glucose (50 microM) caused a rapid loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. Our results indicate that penta-O-galloyl-beta-D-glucose allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA, and induces DFF-45 (DNA fragmentation factor) degradation. These results lead to a working hypothesis that penta-O-galloyl-beta-D-glucose-induced apoptosis is triggered by the release of cytochrome c into the cytosol, procaspase-9 processing, activation of caspase-3, degradation of poly-(ADP-ribose) polymerase, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by penta-O-galloyl-beta-D-glucose may provide a pivotal mechanism for its cancer chemopreventive action.
...
PMID:Induction of apoptosis by penta-O-galloyl-beta-D-glucose through activation of caspase-3 in human leukemia HL-60 cells. 1055 85

Poly(ADP-ribose) polymerase (PARP4) catalyzes the formation of ADP-ribose polymers covalently attached to proteins by using NAD+ as substrate. PARP is strongly activated by DNA single- or double-strand breaks and is thought to be involved in cellular responses to DNA damage. We characterized a dominant negative PARP mutant, i.e. the DNA-binding domain of this enzyme, whose overexpression in cells leads to increased genetic instability following DNA damage. In order to study whether PARP activity is also implicated in the process of tumorigenesis, we generated stably transfected HeLa cell clones with constitutive overexpression of dominant negative PARP and investigated tumor formation of these clones in nude mice. We found that inhibition of PARP activity dramatically reduces tumor forming ability of HeLa cells. Moreover, we provide strong evidence that the observed reduction in tumor forming ability is due to increased tumor cell apoptosis in vivo. Viewed together, our data and those from other groups show that inhibition of PARP enzyme activity interferes with DNA base excision repair and leads to increased genetic instability and recombination but, on the other hand, can sensitize cells to apoptotic stimuli and by this mechanism may prevent tumor formation.
...
PMID:Overexpression of dominant negative PARP interferes with tumor formation of HeLa cells in nude mice: evidence for increased tumor cell apoptosis in vivo. 1059 1

Bcl-2 expression is upregulated in prostate cancer cells after androgen withdrawal and is associated with the development of androgen independence and chemoresistance. Induction of apoptotic cell death after androgen ablation, or chemotherapy, may be enhanced through functional inhibition of bcl-2. In this report, we tested the effects of antisense bcl-2 oligodeoxynucleotides (ODN) with androgen ablation and taxane therapy on time to androgen-independent (Al) progression in the androgen-dependent Shionogi tumor model. Treatment of Shionogi tumor cells in vitro with 500 nmol/L antisense bcl-2 ODN decreased bcl-2 mRNA by 85%, compared with treatment with 500 nmol/L mismatch control ODN. Although bcl-2 expression levels in Shionogi cells were not changed by docetaxel treatment, docetaxel treatment induced bcl-2 phosphorylation. Consequently, the formation of bcl-2/Bax heterodimer formation was inhibited in a dose-dependent manner. Treatment of Shionogi tumors in vitro with either 500 nmol/L antisense bcl-2 ODN or 10 nmol/L docetaxel alone did not induce apoptosis or reduce growth rates. However, combined treatment reduced the concentration that reduces cell viability by 50% (IC50) of docetaxel from 100 nmol/L to 10 nmol/L and induced characteristic apoptotic DNA laddering and cleavage of the poly(ADP-ribose)polymerase (PARP) protein. Adjuvant in vivo administration of antisense bcl-2 ODN and polymeric micellar paclitaxel after castration resulted in a significant delay in time to Al recurrence when compared with administration of either agent alone. Furthermore, combined treatment of mice bearing Al recurrent Shionogi tumors with antisense bcl-2 ODN and micellar paclitaxel synergistically induced tumor regression and growth inhibition when compared with treatment with either agent alone. These findings suggest that down-regulation of bcl-2 by antisense ODN chemosensitizes Al Shionogi tumors to taxanes, over and above the effects of taxane-induced phosphorylation of bcl-2. Antisense bcl-2 ODN combined with taxanes may be a novel approach to the treatment of both established and emerging Al disease.
...
PMID:Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides. 1060 83

Epidemiological studies have shown lower incidence of breast and prostate cancers in Asian populations consuming a traditional diet rich in soy. Protection from these cancers was attributed to the isoflavones, particularly genistein and daidzein found in vivo as the major metabolites of soy isoflavones. However, the role of isoflavones in head and neck cancer is less clear. In our previous studies we reported that genistein can induce cell growth inhibition by arresting the cells at S/G2-M phases, and also induces apoptosis in HN4 squamous cell carcinoma of the head and neck cell line (HNSCC). In this report we show that these changes are accompanied by the down-regulation of Cdk1, and CyclinB1, and up-regulation of the cyclin dependent kinase (Cdk) inhibitor p21WAF1, which may be responsible for the induction of cell cycle arrest and apoptosis. The evidence for the induction of apoptosis was supported by the appearance of DNA ladder as reported previously, and further supported by our current results on the cleavage of poly-ADP-ribose polymerase (PARP), hallmark of apoptosis. This was also accompanied by the up-regulation of Bax, with modest down-regulation of Bcl-2 protein expression, which changes the balance between pro- and anti-apoptosis molecules in favor of pro-apoptosis. Furthermore, we also observed down-regulation and degradation of Cdc25C, which is a marker of cell proliferation, and plays important role in CyclinB-Cdk1 complex activation. The down-regulation followed by the degradation of Cdc25C is an indicator of G2/M arrest and anti-proliferation effects of genistein. Collectively, these data provide strong molecular evidence for the anti-tumor activity of genistein in HNSCC cells.
...
PMID:Genistein induced molecular changes in a squamous cell carcinoma of the head and neck cell line. 1063 78

Green tea polyphenol-(-)epigallocatechin-3-gallate (EGCG)-is a potent chemopreventive agent in many test systems and has been shown to inhibit tumor promotion and induce apoptosis. In this study we describe a novel observation that EGCG displayed strong inhibitory effects on the proliferation and viability of HTB-94 human chondrosarcoma cells in a dose-dependent manner and induced apoptosis. Investigation of the mechanism of EGCG-induced apoptosis revealed that treatment with EGCG resulted in DNA fragmentation, induction of caspase-3/CPP32 activity, and cleavage of the death substrate poly(ADP-ribose)polymerase (PARP). Pretreatment of cells with a synthetic pan-caspase inhibitor (Z-VAD-FMK) and a caspase-3-specific inhibitor (DEVD-CHO) prevented EGCG-induced PARP cleavage. The induction of apoptosis by EGCG via activation of caspase-3/CPP32-like proteases may provide a mechanistic explanation for its antitumor effects.
...
PMID:Involvement of caspase-3 in epigallocatechin-3-gallate-mediated apoptosis of human chondrosarcoma cells. 1077 4

Poly(ADP-ribose) polymerase (PARP) catalyzes the transfer of successive units of ADP-ribose moiety from NAD(+) covalently to itself and other nuclear acceptor proteins. PARP is a zinc finger-containing protein, allowing the enzyme to bind to either double- or single-strand DNA breaks without any apparent sequence preference. The catalytic activity of PARP is strictly dependent on the presence of strand breaks in DNA and is modulated by the level of automodification. Data from many studies show that PARP is involved in numerous biological functions, all of which are associated with the breaking and rejoining of DNA strands, and plays a pivotal role in DNA damage repair. Recent advances in apoptosis research identified PARP as one of the intracellular "death substrates" and demonstrated the involvement of polymerase in the execution of programmed cell death. This review summarizes the biological effects of PARP function that may have a potential for targeted sensitization of tumor cells to genotoxic agents and radiotherapy. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 59-67 (2000).
...
PMID:Poly(ADP-ribose) polymerase in DNA damage-response pathway: implications for radiation oncology. 1081 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---