Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Important roles have been suggested for caspase-8, caspase-9 and Apaf-1 in controlling tumor development and their sensitivity to chemotherapeutic agents. Methylation and deletion of Apaf-1 and CASP8 results in the loss of their expression in melanoma and neuroblastoma, respectively, while CASP9 localization to 1p36.1 suggests it is a good candidate tumor suppressor. The status of CASP9 and Apaf-1 expression in numerous neuroblastoma cell lines with/without amplified MYCN and chromosome 1p36 loss-of-heterozygosity (LOH) was therefore examined to test the hypothesis that one or both of these genes are tumor suppressors in neuroblastoma. Although CASP9 is included in the region encompassing 1p36 LOH in all neuroblastoma cell lines examined, the remaining CASP9 allele(s) express a functional caspase-9 enzyme. Apaf-1 is also expressed in all neuroblastoma tumor cell lines examined. Thus, the CASP9 or Apaf-1 genes do not appear to function as tumor suppressors in MYCN amplified neuroblastomas. However, approximately 20% of the neuroblastoma cell lines with methylated CASP8 alleles are also highly resistant to staurosporine (STS)- and radiation-induced cell death, presumably because cytochrome c is not released from mitochondria. This suggests that a second, smaller sub-group of MYCN amplified neuroblastoma tumors exists with defect(s) in apoptotic signaling components upstream of caspase-9 and Apaf-1. Since no consistent differences in Bcl-2, Bcl-x(L) or Bax expression were seen in the STS- and radiation-resistant neuroblastomas, it suggests that a unique mitochondrial signaling factor(s) is responsible for the defect in cytochrome c release in this sub-group of tumors.
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PMID:Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN. 1189 17

The NFkappaB transcription factors can both promote cell survival and induce apoptosis depending on cell type and context. Neuroblastoma (NB) cells display two predominant culture phenotypes identified as N- and S-types. Malignant S-type cells express neither high levels of MYCN nor Bcl-2, suggesting that other survival mechanisms are important. We characterized NFkappaB activity in S-type cells and determined its role in their survival. S-type lines (SH-EP1 and SK-N-AS) were treated with pyrrolidine dithiocarbamate (PDTC), a NFkappaB inhibitor, or l-1-tosylamido-2-phenylethyl chloromethyl ketone (TPCK), a serine protease inhibitor that blocks IkappaBalpha degradation. Both agents induced cell death, suggesting that constitutive NFkappaB activity is required for survival. The transient expression of a super-repressor IkappaBalpha mutant killed S-type cells. The inhibition of NFkappaB produced an apoptotic response characterized by the collapse of the mitochondrial transmembrane electrochemical gradient, caspase-9 activation, and apoptotic DNA changes. Constitutive NFkappaB DNA binding activity specifically involving p65 and p50 was demonstrated in S- but not N-type cells by electromobility supershift and gene reporter assays. This study demonstrates a role for NFkappaB in the survival of S-type NB tumor cells and suggests that NFkappaB activity and function differ according to NB tumor cell phenotype.
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PMID:Constitutively active NFkappa B is required for the survival of S-type neuroblastoma. 1219 14

The oncogene MYCN is amplified in aggressive neuroblastomas in which caspase-8, an essential component of death receptor pathways, is frequently inactivated, suggesting a critical role of death receptor-mediated apoptosis in suppression of N-Myc oncogenic activity. Elevated levels of N-Myc sensitize neuroblastoma cells to apoptosis induced by various death ligands. Using tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as a model, we define the mechanism underlying the sensitization effect. In neuroblastoma cells with increased expression of N-Myc, TRAIL triggers high levels of caspase-8 activation and Bid cleavage, leading to release of cytochrome c and Smac/DIABLO from mitochondria. However, the apoptotic process requires Smac/DIABLO, but not cytochrome c-mediated caspase-9 activation. N-Myc sensitizes neuroblastoma cells to TRAIL by up-regulating TRAIL receptor-2/DR5/KILLER and Bid. Moreover, DR5 mRNA is increased after N-Myc overexpression, and the human DR5 promoter contains two noncanonical E-boxes critical for the transcriptional activation by N-Myc. These findings establish a mechanistic link between N-Myc and death receptor machinery, which may serve as a checkpoint to guard the cell from N-Myc-initiated tumorigenesis.
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PMID:Linking of N-Myc to death receptor machinery in neuroblastoma cells. 1563 81

The MYC oncogene is frequently deregulated in human tumors, indicative of a poor prognosis because of enhanced resistance to treatment. In such cases, the cellular sensitivity to chemotherapy could be restored by reactivation of Myc-driven apoptosis. We have analyzed apoptosis induced by the cytotoxic agents camptothecin (CPT) and paclitaxel (PTX) using Rat1 fibroblasts with different c-myc status and human Tet21N neuroblastoma cells with conditional MYCN expression. In these cell lines, the drug sensitivity was enhanced by Myc in line with previous reports showing that Myc sensitizes to apoptosis induction by many different apoptosis inducers. CPT-induced apoptosis involved cleavage and activation of proapoptotic Bid and Bax, induction of mitochondrial membrane depolarization, activation of caspase-9 and caspase-3, protein kinase c delta (PKCdelta) signaling and upregulation of p53. We also observed reduced transcriptional activity by Myc and other transcription factors in response to CPT. In contrast, the manner by which Myc potentiates the apoptosis induced by PTX differs from that of CPT and remains to be explored. In summary, our findings revealed that activation of PKCdelta in response to CPT treatment requires Myc and is important in CPT-mediated apoptosis signaling.
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PMID:Camptothecin-induced apoptosis is enhanced by Myc and involves PKCdelta signaling. 1756 38

Neuroblastoma (NB) is the third most common malignancy of childhood, and outcomes for children with advanced disease remain poor; amplification of the MYCN gene portends a particularly poor prognosis. Mxi1 antagonizes N-Myc by competing for binding to Max and E-boxes. Unlike N-Myc, Mxi1 mediates transcriptional repression and suppresses cell proliferation. Mxi1 and Mxi1-0 (an alternatively transcribed Mxi1 isoform) share identical Max and DNA binding domains but differ in amino-terminal sequences. Because of the conservation of these critical binding domains, we hypothesized that Mxi1-0 antagonizes N-Myc activity similar to Mxi1. SHEP NB cells and SHEP cells stably transfected with MYCN (SHEP/MYCN) were transiently transfected with vectors containing full-length Mxi1, full-length Mxi1-0, or the common Mxi domain encoded by exons 2 to 6 (ex2-6). After incubation in low serum, parental SHEP/MYCN cell numbers were reduced compared with SHEP cells. Activated caspase-3 staining and DNA fragmentation ELISA confirmed that SHEP/MYCN cells undergo apoptosis in low serum, while SHEP/MYCN cells transfected with Mxi1 or Mxi1-0 do not. However, SHEP/MYCN cells transfected with Mxi1 or Mxi1-0 and grown in normal serum showed proliferation rates similar to SHEP cells. Mxi ex2-6 did not affect cell number in low or normal serum, suggesting that amino terminal domains of Mxi1 and Mxi1-0 are critical for antagonism. In the absence of N-Myc, Mxi1 and Mxi1-0 induce apoptosis independently through the caspase-8-dependent extrinsic pathway, while N-Myc activates the caspase-9-dependent intrinsic pathway. Together, these data indicate that Mxi1 and Mxi1-0 antagonize N-Myc but also independently impact NB cell survival.
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PMID:Mxi1 and mxi1-0 antagonize N-myc function and independently mediate apoptosis in neuroblastoma. 2574 79