Caspase 8 is absent or low in many ex vivo gliomas

Ashley, David M.; Riffkin, Christopher D.; Muscat, Andrea; Knight, Melissa J.; Kaye, Andrew H.; Novak, Ulrike; Hawkins, Christine J.

doi:10.1002/cncr.21323

Cited by 43 publications

(36 citation statements)

References 78 publications

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“…The results showed that full-length caspase-8 and FLIP protein were both undetectable in untreated U251 and U87 cells, and in anisomycin treated cells, active cleaved caspase-8 was also negative. Ashley et al [21] reported similar results in 2005. They demonstrated that caspase-8 is absent or low in many gliomas, and almost no gliomas express significant amounts of cellular FLIP.…”

Section: Discussionmentioning

confidence: 63%

Anisomycin induces glioma cell death via down-regulation of PP2A catalytic subunit in vitro

Huang

et al. 2012

Acta Pharmacol Sin

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Aim: To examine the effects of anisomycin on glioma cells and the related mechanisms in vitro. Methods: The u251 and u87 human glioblastoma cell lines were tested. The growth of the cells was analyzed using a CCK-8 cell viability assay. Apoptosis was detected using a flow cytometry assay. The expression of proteins and phosphorylated kinases was detected using Western blotting. Results: Treatment of u251 and u87 cells with anisomycin (0.01-8 μmol/L) inhibited the cell growth in time-and concentrationdependent manners (the IC 50 values at 48 h were 0.233±0.021 and 0.192±0.018 μmol/L, respectively). Anisomycin (4 μmol/L) caused 21.5%±2.2% and 25.3%±3.1% of apoptosis proportion, respectively, in u251 and u87 cells. In the two cell lines, anisomycin (4 μmol/L) activated p38 MAPK and JnK, and inactivated ERK1/2. However, neither the p38 MAPK inhibitor SB203580 (10 μmol/L) nor the JnK inhibitor SP600125 (10 μmol/L) prevented anisomycin-induced cell death. On the other hand, anisomycin (4 μmol/L) reduced the level of PP2A/C subunit (catalytic subunit) in a time-dependent manner in the two cell lines. Treatment of the two cell lines with the PP2A inhibitor okadaic acid (100 nmol/L) caused marked cell death. Conclusion: Anisomycin induces glioma cell death via down-regulation of PP2A catalytic subunit. The regulation of PP2A/C exression by anisomycin provides a clue to further study on its role in glioma therapy.

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Section: Discussionmentioning

confidence: 63%

Anisomycin induces glioma cell death via down-regulation of PP2A catalytic subunit in vitro

Huang

et al. 2012

Acta Pharmacol Sin

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“…One hundred thousand cells were lysed, subjected to SDS -PAGE, immunoblotted and signals quantitated using previously published protocols (Ashley et al, 2005). The following antibodies were used: rabbit anti-DR4 and anti-DR5 from ProSci (San Diego, CA, USA) (no.…”

Section: Immunoblottingmentioning

confidence: 99%

“…554021). Control lysates from 293T cells transiently transfected with plasmids directing the expression of caspase-8, FADD, cFLIP L were generated as previously reported (Ashley et al, 2005). Similar control lysates were made using expression plasmids encoding XIAP, DR4 (kindly provided by Paul Ekert) and DR5.…”

Section: Immunoblottingmentioning

confidence: 99%

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In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs

et al. 2008

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TRAIL/Apo-2L has shown promise as an anti-glioma drug, based on investigations of TRAIL sensitivity in established glioma cell lines, but it is not known how accurately TRAIL signalling pathways of glioma cells in vivo are reproduced in these cell lines in vitro. To replicate as closely as possible the in vivo behaviour of malignant glioma cells, 17 early passage glioma cell lines and 5 freshly resected gliomas were exposed to TRAIL-based agents and/or chemotherapeutic drugs. Normal human hepatocytes and astrocytes and established glioma cell lines were also tested. Cross-linked TRAIL, but not soluble TRAIL, killed both normal cell types and cells from three tumours. Cells from only one glioma were killed by soluble TRAIL, although only inefficiently. High concentrations of cisplatin were lethal to glioma cells, hepatocytes and astrocytes. Isolated combinations of TRAIL and chemotherapy drugs were more toxic to particular gliomas than normal cells, but no combination was generally selective for glioma cells. This study highlights the widespread resistance of glioma cells to TRAIL-based agents, but suggests that a minority of high-grade glioma patients may benefit from particular combinations of TRAIL and chemotherapy drugs. In vitro sensitivity assays may help identify effective drug combinations for individual glioma patients.

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“…Gene methylation-independent reduction of caspase-8 expression has also been found in clinical glioma samples. 34 The discovery of an antigen recognized by autologous cytolytic T lymphocytes in oral cavity human squamous cell carcinomas led to the identification of a CASP8 mutation that results in modification of the stop codon and adds an Alu repeat to the CASP8 coding region. 35 CASP8 mutations have also been detected, albeit at relatively low frequency, in colorectal and gastric cancers.…”

Section: Do Individual Caspases Have Tumor Suppressor Functions?mentioning

confidence: 99%

Caspases and cancer

2011

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Evasion of apoptosis is considered to be one of the hallmarks of human cancers. This cell death modality is executed by caspases and several upstream regulatory factors, which direct their proteolytic activity, have been defined as either tumor suppressors or oncogenes. Often these regulatory factors, in addition to being potent apoptosis inducers, function in cell survival or repair signaling pathways in response to cellular stress. Thus, loss of function in a distinct regulatory mechanism does not necessarily mean that tumor formation is due to apoptosis malfunction resulting from insufficient caspase activation. Although each caspase has been assigned a distinct role in apoptosis, some redundancy with respect to their regulatory functions and substrate recognition is evident. Jointly, these proteases could be considered to possess solid tumor suppressor function, but what is the evidence that deregulation of specific caspases per se induces inappropriate cell survival, leading to enhanced tumorigenic potential? This question will be addressed in this review, which covers basic molecular mechanisms derived from in vitro analyses and emphasizes new insights that have emerged from in vivo and clinical studies. In organisms, excess cells during development, as well as potentially harmful cells resulting from pathophysiological conditions, are eliminated by various cell death modalities. Among them, apoptosis is the most investigated, and almost 40 years ago, it was described as a major defense strategy that prevents cells from acquiring tumorigenic potential. 1 This suicide mechanism is controlled by multiple and interrelated pathways ensuring that caspases, the proteolytic initiators and executioners of apoptosis, are triggered only in cells requiring termination. There is overwhelming experimental evidence supporting the idea that disturbances in the regulation of caspase activation are central for the avoidance of cancer cell death, both in vitro and in vivo. However, what evidences suggest that caspases per se act as tumor suppressors? It was reported that cells do not necessarily undergo caspaseindependent cell death in the absence of active caspases, but may instead survive insult and even promote clonogenic tumor growth. 2 Yet, it was unclear which individual caspases could fulfill this function. Recently, certain initiator caspases have been suggested as putative tumor suppressor genes. 3,4 This review is focusing on caspases and their role in tumor suppression, and emphasizing new evidences that have emerged from in vivo observations and clinical material, taking into consideration supporting in vitro data that has enlightened basic molecular mechanisms. CaspasesClassification of human caspases is based either on their function, the size of their pro-domain or cleavage specificity.Considering the first criteria, caspase-1, -4 and -5 belong to the group I (inflammatory) caspases that are involved in cytokine maturation. These proteases are primarily associated with the innate immunity against pathogens an...

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Caspase 8 is absent or low in many ex vivo gliomas

Cited by 43 publications

References 78 publications

Anisomycin induces glioma cell death via down-regulation of PP2A catalytic subunit in vitro

Anisomycin induces glioma cell death via down-regulation of PP2A catalytic subunit in vitro

In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs

Caspases and cancer

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