Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells

Knight, Melissa J.; Riffkin, Christopher D.; Muscat, Andrea; Ashley, David M.; Hawkins, Christine J.

doi:10.1038/sj.onc.1204810

Cited by 94 publications

(106 citation statements)

References 58 publications

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“…Cell lines that were highly susceptible to both FasL and TRAIL (SF767 and SF210) expressed high levels of caspase-8 and low levels of c-FLIP, whereas cells that were resistant to both death ligands (U343MG and U373MG) expressed low levels of caspase-8 and high levels of at least one c-FLIP isoform. Based on our results, as well as those published previously, 34,61,62 we conclude that while the majority of BTs have a functional Fas and/or TRAIL apoptotic pathway, a certain fraction of them (between 25 and 35%) are resistant through a number of different apoptotic pathway alterations. [37][38][39][61][62][63][64] However, high caspase-8:c-FLIP ratio was not in itself indicative of high sensitivity to either FasL-GFP or to TRAIL.…”

Section: Discussionsupporting

confidence: 90%

“…Based on our results, as well as those published previously, 34,61,62 we conclude that while the majority of BTs have a functional Fas and/or TRAIL apoptotic pathway, a certain fraction of them (between 25 and 35%) are resistant through a number of different apoptotic pathway alterations. [37][38][39][61][62][63][64] However, high caspase-8:c-FLIP ratio was not in itself indicative of high sensitivity to either FasL-GFP or to TRAIL. These observations are consistent with the general mechanism of receptor-ligand-mediated signal transduction, where multiple components have to interact to propagate the signal, and conversely the signal can be blocked or degraded by mutations or dysregulation of those components.…”

Section: Discussionsupporting

confidence: 90%

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Enhanced apoptosis of glioma cell lines is achieved by co-delivering FasL-GFP and TRAIL with a complex Ad5 vector

Rubinchik

Woraratanadharm

et al. 2003

Cancer Gene Ther

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Brain tumors (BTs) are among the most malignant forms of human cancer. Unfortunately, current treatments are often ineffective and produce severe side effects. Cytotoxic gene therapy is an alternative treatment strategy, with the potential advantages of reduced toxicity to normal brain tissue. Apoptosis-inducing ''death ligands'' Fas ligand and TNF-related apoptosis-inducing ligand (TRAIL) are genes with substantial cytotoxic activity in susceptible tumor cells. Here, we compared the effectiveness of Ad vectormediated delivery of Fas ligand-green fluorescent protein (FasL-GFP) fusion protein, human TRAIL, and both genes simultaneously. We examined a panel of 13 cell lines (eight derived from primary isolates) for susceptibility to Ad5-based vector infection and for sensitivity to FasL-and TRAIL-mediated apoptosis. All cell lines were efficiently transduced, but, as expected, varied in their sensitivity to ligand-induced apoptosis. Generally, sensitivity to FasL-GFP correlated with cell surface FasR levels, but no such correlation was seen for TRAIL and its functional receptors, DR4 and DR5. The vector expressing both FasL-GFP and TRAIL was more effective than either of the single-gene vectors at comparable transduction levels, and it was effective against a broader range of cell lines. In five cell lines, coexpression resulted in apoptosis levels greater than those predicted for strictly additive activity of the two death ligands. We believe that Ad vector-mediated delivery of multiple death ligands may be developed as a potential BT therapy, either alone or in conjunction with surgical resection of the primary tumor.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

Enhanced apoptosis of glioma cell lines is achieved by co-delivering FasL-GFP and TRAIL with a complex Ad5 vector

Rubinchik

Woraratanadharm

et al. 2003

Cancer Gene Ther

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“…When cells appeared to have reached 50% confluence or maximal confluency in a T25 flask for that cell line, they were expanded into a T75 flask (passage 2). Cells were also expanded into a T75 (passage 3) flask when they reached 50% (Knight et al, 2001(Knight et al, , 2004. LN18 cells were purchased from the ATCC (Manassas, VA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Inhibition of IAP activity in type II glioma cells sensitised them to TRAIL (Fulda et al, 2002b), indicating that IAP activity contributed to the TRAIL resistance of those lines. Low levels of caspase-8 may also contribute to TRAIL resistance (Knight et al, 2001;Ashley et al, 2005;Eramo et al, 2005).…”

mentioning

confidence: 99%

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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“…First, we assessed cleavage products and apoptosis in the caspase-8-deficient cell line U373MG. U373MG has extremely low levels of normal, wild type caspase-8, which makes it resistant to death-ligands (Knight et al, 2001). Despite high levels of IRF-1 expression by immunoblotting, there is no effect on the levels of procaspase-8 and no caspase-8, -3, or -7 cleavage products ( Figure 5a).…”

Section: Screening For Individual Caspases Involved In Irf-1-induced mentioning

confidence: 99%

Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells

et al. 2007

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Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that has apoptotic anti-tumor activity. In breast cancer cell types, IRF-1 is implicated in mediating apoptosis by both novel and established anti-tumor agents, including the anti-estrogens tamoxifen and faslodex. Here we demonstrate that in MDA468 breast cancer cells, apoptosis by IFN-c is mediated by IRF-1 and IFN-c, and IRF-1-induced apoptosis is caspase-mediated. IRF-1 induction results in cleavage of caspase-8, -3 and -7, and application of caspase inhibitors attenuate activated cleavage products. IRF-1-induced apoptosis involves caspase-8 since apoptosis is significantly decreased by the caspase-8-specific inhibitor IETD, c-FLIP expression and in caspase-8-deficient cancer cells. Furthermore, we demonstrate that IRF-1-induced apoptosis requires fas-associated death domain (FADD) since dominant-negative FADD expressing cells resist IRF-1-induced apoptosis and activated downstream products. Immunofluorescent studies demonstrate perinuclear colocalization of FADD and caspase-8. Despite the known role of FADD in mediating death-ligand induced apoptosis, neutralizing antibodies against classical death receptors do not inhibit IRF-1 induced apoptosis, and no secreted ligand appears to be involved since MDA468 coincubated with IRF-1 transfected cells do not apoptose. Therefore, we demonstrate that IRF-1 induces a ligand-independent FADD/caspase-8-mediated apoptosis in breast cancer cells.

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Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells

Cited by 94 publications

References 58 publications

Enhanced apoptosis of glioma cell lines is achieved by co-delivering FasL-GFP and TRAIL with a complex Ad5 vector

Enhanced apoptosis of glioma cell lines is achieved by co-delivering FasL-GFP and TRAIL with a complex Ad5 vector

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

Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells

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