UMLS:C0027651 - FACTA Search

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

We analyzed a set of 103 non-small cell lung carcinomas (NSCLCs) for caspase-3, -6 and -8 expression and apoptosis. Additionally, the expression of bcl-2, bax and p53 were studied. Caspase-3 positivity appeared as diffuse, cytoplasmic staining and was restricted to the tumor area. In contrast, the immunoreactivity for caspase-6 was intense, granular and mostly located in single cells or groups of tumor cells showing apoptotic morphology. The caspase-8 expression pattern was a combination of the two other caspases studied, featuring both diffuse and single-cell patterns restricted to the tumor area. No significant differences were seen in caspase -3, -6 and -8 expression between tumors of different histological types or grades. The number of apoptotic cells and bodies was significantly higher in NSCLCs, in which caspase-8 immunostaining was mainly seen in single cells (p = 0.017), whereas caspase -3 and -6 expression had no association with apoptosis. It is apparent that, in lung tissue, up-regulation of caspase expression is a phenomenon associated solely with neoplasia and reflects the readiness of the tumor cells to undergo apoptosis. Interestingly, caspases -3, -6 and -8 each have an individual staining pattern in NSCLC, perhaps reflecting their different position in the caspase hierarchy.
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PMID:Expression of caspases-3, -6 and -8 and their relation to apoptosis in non-small cell lung carcinoma. 1141 Aug 65

Resveratrol, a naturally occurring plant antibiotic has been the focus of a number of studies investigating its biological attributes, which include anti-oxidant activity, anti-platelet aggregation effect, anti-atherogenic property, estrogen-like growth promoting effect, growth inhibiting activity, immunomodulation, and chemoprevention. More recently, since the first report on the apoptosis inducing activity of resveratrol in human cancer cells, the interest in this molecule as a potential chemotherapy agent has significantly intensified. Not only has its role as an anti-cancer agent been corroborated, but the precise mechanism(s) of the anti-cancer activity of resveratrol is/are being elucidated. Our group has been active in studying the cross talk between the caspase family of proteases and mitochondria, in drug-induced apoptosis. In this regard, we have shown that the cancer preventive activity of resveratrol could be attributed to its ability to trigger apoptosis in human leukemia and breast carcinoma cells. The cytotoxicity of resveratrol is restricted against these transformed cell types due to its ability to selectively upregulate CD95-CD95L interaction on the tumor cell surface, unlike normal peripheral blood cells. Despite the involvement of the CD95 signaling pathway, apoptosis induced by resveratrol is not accompanied by robust caspase 8 activation, but involves mitochondrial release of cytochrome C and downstream activation of caspases 9 and 3. We also extrapolate these in vitro findings in a murine model of carcinogensis, and demonstrate in vivo induction of apoptosis in mouse skin papillomas. These findings highlight the chemotherapeutic potential of this polyphenolic compound.
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PMID:Resveratrol--from the bottle to the bedside? 1142 22

Interferons (IFNs) and retinoids are potent tumor growth suppressors. We have shown earlier that the IFN-beta and all-trans retinoic acid combination, but not the single agents, induces death in several tumor cell lines. Employing a genetic approach we have recently identified several Genes associated with Retinoid-IFN induced Mortality (GRIM) that mediate the cell death effect of IFN/RA combination. One of the GRIMs, GRIM-12, was identical to human thioredoxin reductase (TR), an enzyme that controls intracellular redox state. To define the participants of TR mediated death pathway we have examined the role of thioredoxin (Trx), its downstream substrate, and its influence on IFN/RA-induced death regulation. Inhibition of the thioredoxin expression by antisense RNA suppressed cell death. Similarly, a mutant Trx1 lacking the critical cysteine residues blocked cell death. In contrast, overexpression of wildtype thioredoxin augmented cell death. This effect of Trx1 was in part due to its ability to augment cell death via caspase-8. The redox inactive Trx1 mutant inhibits the cell death induced by caspase-8 but not caspase-3. These studies identify a novel mechanism of cell death regulation by IFN/RA combination involving redox enzymes.
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PMID:Thioredoxin participates in a cell death pathway induced by interferon and retinoid combination. 1143 33

Death ligands (TNF, FasL, TRAIL) and their respective death receptor signaling pathways can be used to induce tumor cells to undergo apoptosis. Chemotherapeutic drugs can induce apoptosis and the upregulation of death ligands or their receptors. Downstream events following cytotoxic stress-induced DNA damage and the signaling pathways that lead to the induction of apoptosis may be either dependent or independent of death receptor signaling. The involvement of the Fas signaling pathway in chemotherapy-induced apoptosis has been the most extensively studied, with the current emergence of information on the TRAIL signaling pathway. Fas-mediated and chemotherapy-induced apoptosis can converge at the level of the receptor, FasL, DISC formation, activation of the initiator caspase-8, at the level of the mitochondria, or at the level of downstream effector caspase activation. Convergence is influenced by the specific form of DNA damage, the cellular environment, and the specific pathway(s) by which death receptor-mediated or drug-mediated apoptosis are induced. This review discusses the different levels of interaction between signaling pathways in the different forms of cell death.
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PMID:Shared pathways: death receptors and cytotoxic drugs in cancer therapy. 1145 71

We previously reported a high incidence of loss of heterozygosity (LOH) on chromosome 2q33 in neuroblastoma (NB), observed in various types of human cancers including lung cancer, head and neck cancer and follicular thyroid carcinoma. To better elucidate the role of chromosome 2q aberrations in NB, we examined common allelic imbalance (AI) regions on chromosome 2q in 82 NB patients using 10 polymorphic microsatellite markers. AI on 2q was detected in 26 (32%) of 82 NB cases. There was a distinct common AI region between the D2S115 and D2S307 markers on 2q33. The distance between these markers was about 2.0 cM. Recently, the caspase 8 and caspase 10 genes, both of which encode cystein protease, were mapped to chromosome 2q33. Since the common AI region on 2q33 includes the caspase 8 and caspase 10 genes, the alterations of these genes were examined further. Absent or reduced expression of caspase 8 and caspase 10 were found in 19 (70%) of 27 and two (7%) of 27 NB cell lines by reverse transcription-polymerase chain reaction, respectively. A missense mutation was detected at codon 96, GCT (Alanine) to GTT (Valine), of the caspase 8 gene in one of the NB cell lines lacking caspase 8 expression. Thirteen (68%) of 19 cell lines lacking caspase 8 expression displayed methylation of the CpG island of the caspase 8 gene, whereas only one (13%) of eight cell lines with caspase 8 expression showed caspase 8 methylation (P=0.031). Furthermore, there was a significant association between AI at 2q33 and loss of caspase 8 expression (P=0.026). These results indicated that there was a tumor suppressor gene in the common AI region on chromosome 2q33 involved in the pathogenesis of a subset of NB. It is possible that the caspase 8 gene is one of the candidate tumor suppressor genes for NB and inactivation of this gene plays an important role in the tumorigenesis of NB through mainly its methylation.
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PMID:Allelic imbalance on chromosome 2q and alterations of the caspase 8 gene in neuroblastoma. 1146 26

Epigallocatechin gallate (EGCG) is known to induce apoptosis in various types of tumor cells, but the precise mechanism by which EGCG induces apoptosis remains to be elucidated. The Fas-Fas ligand system is one of the major pathways operating in the apoptotic cascade. The aim of this study was to examine the possibility that EGCG-binding to Fas triggers the Fas-mediated apoptosis. The EGCG treatment of human monocytic leukemia U937 cells resulted in elevation of caspase 8 activity and fragmentation of caspase 8. The DNA ladder formation caused by the EGCG treatment was inhibited by the caspase 8 inhibitor. These findings suggested the involvement of the Fas-mediated cascade in the EGCG-induced apoptosis in U937 cells. Affinity chromatography revealed the binding between EGCG and Fas. Thus, the results suggest that EGCG-binding to Fas, presumably on the cell surface, triggers the Fas-mediated apoptosis in U937 cells.
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PMID:Apoptosis induction by epigallocatechin gallate involves its binding to Fas. 1147 67

Apoptosis is required for proper tissue homeostasis. Defects in apoptosis signaling pathways, thus, contribute to carcinogenesis and chemoresistance. A major goal in chemotherapy is, therefore, to find cytotoxic agents that restore the ability of tumor cells to undergo apoptosis. We show here that the sesquiterpene lactone helenalin (10-50 microM) induces apoptosis in leukemia Jurkat T cells even if they lack the CD95 death receptor or overexpress the antiapoptotic proteins Bcl-x(L) or Bcl-2. Activated peripheral blood mononuclear cells, however, are not affected (10-50 microM helenalin). Helenalin led to a time-dependent (0-24 h) cleavage of the specific caspase-3-like substrate Asp-Glu-Val-Asp-7-amino-4-trifluoromethylcoumarin as well as to the proteolytic processing of procaspase-3 and -8. Caspase activation was a necessary requirement for apoptosis because the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk, 50 microM) completely abrogated helenalin-induced DNA fragmentation as well as phosphatidylserin translocation. Although the initiator caspase-8 was activated, the helenalin-induced signaling pathway did not require the CD95 death receptor as shown using cells without or with an antibody (ZB4)-blocked CD95 receptor. Helenalin also did not induce CD95 or CD95-ligand expression. On the other hand, helenalin was found to induce the release of cytochrome c from mitochondria that was not inhibited by the caspase inhibitor zVAD-fmk, which indicated that cytochrome c release precedes caspase activation. Cytochrome c release was accompanied by dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), which was partly inhibited by zVAD-fmk, which suggests that caspases are involved in loss of DeltaPsi(m). Most importantly, overexpression of the mitochondria protecting proteins Bcl-x(L) or Bcl-2 failed to confer resistance to helenalin-induced apoptosis, although the data presented here suggest that helenalin induces a mitochondria-dependent pathway. Thus, helenalin is a promising experimental cytotoxic agent that possibly points to new strategies to overcome apoptosis resistance attributable to overexpression of antiapoptotic Bcl-2 proteins.
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PMID:Helenalin triggers a CD95 death receptor-independent apoptosis that is not affected by overexpression of Bcl-x(L) or Bcl-2. 1147 21

The p53 tumor suppressor plays a key role in the cell's response to genotoxic stress and loss of this 'guardian of the genome' is an important step in carcinogenesis. The ability of p53 to induce apoptosis through transactivation of its target genes is critical for its function as tumor suppressor. We have found that overexpression of p53 in human cancer cell lines resulted in apoptosis as measured by PARP cleavage. Furthermore we observed cleavage of both caspase 9 and caspase 8 after overexpression of p53 and found that p53-dependent apoptosis was inhibited by either cellular (c-Flip-s, Bcl-X(L)) or pharmacological inhibitors of caspase 8 or caspase 9 respectively. These results indicate that p53 is mediating apoptosis through both the mitochondrial and death receptor pathways. To elucidate the relevant p53 target genes and examine the caspase pathways utilized in vivo, we treated p53+/+ and age matched p53-/- mice with 5 Gy ionizing radiation or 0.5 mg/animal dexamethasone and harvested tissues at 0, 6 and 24 h. We examined the mRNA expression of p21, bax, KILLER/DR5, FAS/APO1 and EI24/PIG8 using TaqMan real time quantitative RT-PCR in the spleen, thymus and small intestine. Although the basal mRNA levels of these genes did not depend on the presence of p53, we observed a p53-dependent induction of all these targets in response to gamma-irradiation and a p53-independent regulation for p21 and KILLER/DR5 in response to dexamethasone. Furthermore, we have demonstrated that the relative induction of these p53 target genes is tissue specific. Despite observing otherwise similar levels of death in these tissues, our findings suggest that in some cases apoptosis mediated through p53 occurs by redundant pathways or by a 'group effect' while in other tissues one or few targets may play a key role in p53-dependent apoptosis. Surprisingly, KILLER/DR5 is the dominantly induced transcript in both the spleen and small intestine suggesting a potentially important role for this p53 target gene in vivo.
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PMID:Tissue specific expression of p53 target genes suggests a key role for KILLER/DR5 in p53-dependent apoptosis in vivo. 1149 83

FLIP (FLICE Inhibitory Protein) is a recently identified intracellular inhibitor of caspase-8 activation that potently inhibits cell death mediated by all death receptors including Fas and TRAIL. FLIP has recently been shown to favor tumor growth and immune escape in mouse tumor models. We analyzed FLIP expression by immunohistochemistry in a panel of 61 benign and malignant human melanocytic skin lesions. FLIP expression was undetectable in all but one benign melanocytic lesion (31/32, 97%). In contrast, FLIP was strongly expressed in most melanomas (24/29 = 83%). Overexpression of FLIP by transfection in a Fas- and TRAIL-sensitive human melanoma cell line rendered this cell line more resistant to death mediated by both TRAIL and FasL. Selective expression of FLIP by human melanomas may confer in vivo resistance to FasL and TRAIL, thus representing an additional mechanism by which melanoma cells escape immune destruction.
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PMID:Selective expression of FLIP in malignant melanocytic skin lesions. 1151 16

Neuroblastomas that overexpress N-Myc due to amplification of the MYCN oncogene are aggressive tumors that become very resistant to treatment by chemotherapy and irradiation. to identify tumor suppressor genes in this group of neuroblastomas we analyzed the expression and function of both apoptosis-related cell cycle regulatory genes in cell lines and patient tumor samples. We found that in a high percentage of neuroblastoma cell lines and patient samples with amplified MYCN, caspase-8 mRNA is not expressed. The caspase-8 gene, CASP8, was deleted or silenced by methylation in the neuroblastoma cell lines while methylation of its promoter region was the predominant mechanism for its inactivation in the patient tumor samples. Reintroduction of caspase-8 into the neuroblastoma cell lines resensitized these cells to drug-induced and survival factor dependent apoptosis. Subsequently others have also shown that caspase-8 is silenced by methylation in neuroblastoma and peripheral neural ectodermal tumors, and that the caspase-9 regulator Apaf-1 is silenced by methylation in melanoma cell lines and patient samples. We conclude that caspase-8 acts as a tumor suppressor gene in neuroblastomas, that its silencing provides a permissive environment for MYCN gene amplification once the tumors are treated with chemotherapeutic drugs/irradiation, and that expression of this gene in these tumor cells may be of clinical benefit. We also discuss the possible significance of the neural crest cell progenitor cell origin and the silencing of important apoptotic regulators via methylation in both neuroblastoma and melanoma tumors.
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PMID:Aggressive childhood neuroblastomas do not express caspase-8: an important component of programmed cell death. 1151 73

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