Loss of caspase‐8 expression in neuroblastoma is related to malignancy and resistance to TRAIL‐induced apoptosis

Hopkins‐Donaldson, Sally; Bodmer, Jean‐Luc; Bourloud, Katia Balmas; Brognara, Christine Beretta; Tschopp, Jürg; Groß, Nicole

doi:10.1002/1096-911x(20001201)35:6<608::aid-mpo25>3.3.co;2-l

Cited by 28 publications

(45 citation statements)

References 11 publications

(15 reference statements)

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“…However, other reports have indicated that several neuroblastoma cell lines are resistant to TRAIL-induced apoptosis. 26 Variation among neuroblastoma cell lines in sensitivity to TRAIL may be due to differences in expression levels of certain components of the TRAIL pathway. 27 For example, several neuroblastoma tumors and cell lines fail to express caspase-8.…”

Section: Delivery Of Trail Via An Adenoviral Vector Induces Apoptosismentioning

confidence: 99%

“…27 For example, several neuroblastoma tumors and cell lines fail to express caspase-8. 28 Alternatively, the differences in sensitivity may be due to epigenetic factors, such as the methylation of caspase-8, 26,28,29 which may substantially alter the ability of TRAIL to induce apoptosis. However, lack of TRAIL receptor expression prevented 27 suggesting that integrity of the entire TRAIL pathway is necessary for its function.…”

Section: Delivery Of Trail Via An Adenoviral Vector Induces Apoptosismentioning

confidence: 99%

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Inhibition of the NF-κB pathway enhances TRAIL-mediated apoptosis in neuroblastoma cells

et al. 2004

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Neuroblastoma is the most common solid extracranial neoplasm in children and causes many deaths. Despite treatment advances, prognosis for neuroblastoma remains poor, and a critical need exists for the development of new treatment regimens. TNF-related apoptosis-inducing-ligand (TRAIL) induces cell death in a variety of tumors, but not in normal tissues. Moreover, TRAIL is nontoxic, making it a strong antitumor therapeutic candidate. We demonstrate that introduction of the TRAIL gene into neuroblastoma cell lines using an adenoviral vector leads to apoptotic cell death. RT-PCR and flow-cytometric analyses demonstrated that TRAIL's effect is mediated primarily via the TRAIL R2 receptor. As TRAIL can activate the nuclear factor-kB (NF-kB) signaling pathway, which can exert an antiapoptotic effect, we hypothesized that inhibition of NF-kB signaling may augment TRAIL's killing effects. TRAIL-mediated cell death was enhanced when neuroblastoma cells were simultaneously infected with a dominant-negative mutant of IkB kinase, a kinase essential for NF-kB activation. The combination of blockade of NF-kB signaling and expression of TRAIL induced apoptotic death in a greater proportion of SKNSH cells than did either treatment alone. Thus, concurrent inhibition of the NF-kB pathway and the induction of TRAIL-mediated apoptosis may become a useful approach for the treatment of neuroblastoma.

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Section: Delivery Of Trail Via An Adenoviral Vector Induces Apoptosismentioning

confidence: 99%

Section: Delivery Of Trail Via An Adenoviral Vector Induces Apoptosismentioning

confidence: 99%

Inhibition of the NF-κB pathway enhances TRAIL-mediated apoptosis in neuroblastoma cells

et al. 2004

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“…In the present study we investigated the mechanism of dox-induced death in N-type NB cell lines LAN-1 and IMR-32, which are silenced for caspase-8 expression, amplified for N-myc, and are completely resistant to TNF-related apoptosis inducing-ligand (TRAIL)-induced death (Hopkins-Donaldson et al, 2000). We also assessed the role of the death receptor pathway in dox-induced death of the S-type NB cell line SH-EP used previously by Fulda et al (1998) which are highly sensitive to TRAIL-induced death (Hopkins-Donaldson et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…We also assessed the role of the death receptor pathway in dox-induced death of the S-type NB cell line SH-EP used previously by Fulda et al (1998) which are highly sensitive to TRAIL-induced death (Hopkins-Donaldson et al, 2000). Cell viability tests were performed in order to compare the sensitivity to dox-induced death of N-type and S-type NB cell lines.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin-induced death in neuroblastoma does not involve death receptors in S-type cells and is caspase-independent in N-type cells

et al. 2002

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Death induced by doxorubicin (dox) in neuroblastoma (NB) cells was originally thought to occur via the Fas pathway, however since studies suggest that caspase-8 expression is silenced in most high stage NB tumors, it is more probable that dox-induced death occurs via a different mechanism. Caspase-8 silenced N-type invasive NB cell lines LAN-1 and IMR-32 were investigated for their sensitivity to dox, and compared to S-type noninvasive SH-EP NB cells expressing caspase-8. All cell lines had similar sensitivities to dox, independently of caspase-8 expression. Dox induced caspase-3, -7, -8 and -9 and Bid cleavage in S-type cells and death was blocked by caspase inhibitors but not by oxygen radical scavenger BHA. In contrast, dox-induced death in Ntype cells was caspase-independent and was inhibited by BHA. Dox induced a drop in mitochondrial membrane permeability in all cell lines. Dox-induced death in Stype cells gave rise to apoptotic nuclei, whereas in Ntype cells nuclei were non-apoptotic in morphology. Transfection of SH-EP cells with a dominant negative FADD mutant inhibited TRAIL-induced death, but had no effect on dox-induced apoptosis. These results suggest that S-type cells undergo apoptosis after dox treatment independently of death receptors, whereas N-type cells are killed by a caspase-independent mechanism.

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“…The other four cell lines show differential patterns of loss. The primers and experimental conditions were as described before (Griffith et al, 1998;Hopkins-Donaldson et al, 2000;Ng et al, 1999;O'Connell et al, 1996). (b) Re-expression of CASP and CASP10 as demonstrated by RT -PCR after Aza-CdR treatment (Shivapurkar et al, 2002).…”

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confidence: 99%

Loss of expression of death-inducing signaling complex (DISC) components in lung cancer cell lines and the influence of MYC amplification

Shivapurkar

Reddy²,

Matta³

et al. 2002

Oncogene

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We have previously reported that the key apoptosis related gene caspase 8 (CASP8) is frequently silenced in small cell lung cancer (SCLC) tumors and cell lines usually, but not always, by aberrant promoter methylation. Because CASP8 is a key component of the deathinducing signaling complex (DISC) when specific death receptors (including DR4, DR5, FAS) are activated by their specific ligands (TRAIL/FASL), we examined expression of the components of the DISC complex in lung cancer cell lines. MYC family members are frequently amplified (MYC+ve) in SCLC, and MYC is a potent inducer of apoptosis. We examined 34 SCLC lines (12 of which were MYC+ve) and 22 NSCLC lines. CASP8 gene expression was frequently lost (79%) at message and protein levels in SCLC but not in non-SCLC (NSCLC). MYC amplification was present in 45% of SCLC cell lines, which had lost CASP8 expression, but not in any of the CASP8 positive lines. The frequency of CASP8 loss was significantly higher in MYC+ve SCLC compared to MYC7ve SCLC or in NSCLC. Analyses of other DISC components showed significantly higher rates of loss of expression of CASP10, DR5, FAS and FASL in SCLC compared to NSCLC. The loss of expression of proapoptotic DISC components was significantly higher in MYC+ve SCLC cell lines and these lines were completely resistant to TRAIL. Expression of CASP10 (a caspase closely related to CASP8) was frequently absent at the protein level in both SCLC and NSCLC lines. Expression of c-FLIP (proteolytically inactive homolog of CASP8) was inversely related to expression of CASP8. Our major conclusions are: (a) The death receptor pathway is differently inactivated at multiple levels in lung cancer cell lines; and (b) MYC amplification in SCLC is associated with inactivation of most components of the DISC complex, with resistance to TRAIL and with expression of c-FLIP. These findings may have considerable clinical and therapeutic implications.

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Loss of caspase‐8 expression in neuroblastoma is related to malignancy and resistance to TRAIL‐induced apoptosis

Cited by 28 publications

References 11 publications

Inhibition of the NF-κB pathway enhances TRAIL-mediated apoptosis in neuroblastoma cells

Inhibition of the NF-κB pathway enhances TRAIL-mediated apoptosis in neuroblastoma cells

Doxorubicin-induced death in neuroblastoma does not involve death receptors in S-type cells and is caspase-independent in N-type cells

Loss of expression of death-inducing signaling complex (DISC) components in lung cancer cell lines and the influence of MYC amplification

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