Fenretinide-induced caspase-8 activation and apoptosis in an established model of metastatic neuroblastoma.

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Ressource 1Download: BMC Cancer 2009.pdf (1041.08 [Ko])
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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_19AF794B5C18
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Fenretinide-induced caspase-8 activation and apoptosis in an established model of metastatic neuroblastoma.
Journal
BMC cancer
Author(s)
Raguénez G, Mühlethaler-Mottet A, Meier R, Duros C, Bénard J, Gross N
Publication state
Published
Issued date
03/2009
Peer-reviewed
Oui
Language
english
Abstract
Background
Resistance of high-risk metastatic neuroblastoma (HR-NB) to high dose chemotherapy (HD-CT) raises a major therapeutic challenge in pediatric oncology. Patients are treated by maintenance CT. For some patients, an adjuvant retinoid therapy is proposed, such as the synthetic retinoid fenretinide (4-HPR), an apoptotic inducer. Recent studies demonstrated that NB metastasis process is enhanced by the loss of caspase-8 involved in the Integrin-Mediated Death (IMD) process. As the role of caspase-8 appears to be critical in preventing metastasis, we aimed at studying the effect of 4-HPR on caspase-8 expression in metastatic neuroblasts.
Methods
We used the human IGR-N-91 MYCN-amplified NB experimental model, able to disseminate in vivo from the primary nude mouse tumor xenograft (PTX) into myocardium (Myoc) and bone marrow (BM) of the animal. NB cell lines, i.e., IGR-N-91 and SH-EP, were treated with various doses of Fenretinide (4-HPR), then cytotoxicity was analyzed by MTS proliferation assay, apoptosis by the propidium staining method, gene or protein expressions by RT-PCR and immunoblotting and caspases activity by colorimetric protease assays.
Results
The IGR-N-91 parental cells do not express detectable caspase-8. However the PTX cells established from the primary tumor in the mouse, are caspase-8 positive. In contrast, metastatic BM and Myoc cells show a clear down-regulation of the caspase-8 expression. In parallel, the caspases -3, -9, -10, Bcl-2, or Bax expressions were unchanged. Our data show that in BM, compared to PTX cells, 4-HPR up-regulates caspase-8 expression that parallels a higher sensitivity to apoptotic cell death. Stable caspase-8-silenced SH-EP cells appear more resistant to 4-HPR-induced cell death compared to control SH-EP cells. Moreover, 4-HPR synergizes with drugs since apoptosis is restored in VP16- or TRAIL-resistant-BM cells. These results demonstrate that 4-HPR in up-regulating caspase-8 expression, restores and induces apoptotic cell death in metastatic neuroblasts through caspase-8 activation.
Conclusion
This study provides basic clues for using fenretinide in clinical treatment of HR-NB patients. Moreover, since 4-HPR induces cell death in caspase-8 negative NB, it also challenges the concept of including 4-HPR in the induction of CT of these patients.
Keywords
Bone Marrow Cell, Fenretinide, Synthetic Retinoid, Primary Tumor Xenograft
Pubmed
Open Access
Yes
Create date
23/03/2020 12:44
Last modification date
26/06/2020 7:08
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