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Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma

Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family prote...

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Autores principales: Fianco, Giulia, Contadini, Claudia, Ferri, Alessandra, Cirotti, Claudia, Stagni, Venturina, Barilà, Daniela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320982/
https://www.ncbi.nlm.nih.gov/pubmed/30501030
http://dx.doi.org/10.3390/ijms19123798
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author Fianco, Giulia
Contadini, Claudia
Ferri, Alessandra
Cirotti, Claudia
Stagni, Venturina
Barilà, Daniela
author_facet Fianco, Giulia
Contadini, Claudia
Ferri, Alessandra
Cirotti, Claudia
Stagni, Venturina
Barilà, Daniela
author_sort Fianco, Giulia
collection PubMed
description Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dependent phosphorylation of Caspase-8 on Tyr380. Loss of apoptotic signaling is a hallmark of cancer and indeed Caspase-8 expression is often lost in tumors. This event may account not only for cancer progression but also for cancer resistance to radiotherapy and chemotherapy. Intriguingly, other tumors, such as glioblastoma, preferentially retain Caspase-8 expression, and high levels of Caspase-8 expression may correlate with a worse prognosis, suggesting that in this context this protease loses its apoptotic activity and gains additional functions. Using different cellular systems, it has been clearly shown that in cancer Caspase-8 can exhibit non-canonical functions, including promotion of cell adhesion, migration, and DNA repair. Intriguingly, in glioblastoma models, Caspase-8 can promote NF-κB-dependent expression of several cytokines, angiogenesis, and in vitro and in vivo tumorigenesis. Overall, these observations suggest that some cancer cells may hijack Caspase-8 function which in turn promote cancer progression and resistance to therapy. Here we aim to highlight the multiple functions of Caspase-8 and to discuss whether the molecular mechanisms that modulate the balance between those functions may be targeted to dismantle the aberrant activity of Caspase-8 and to restore its canonical apoptotic functionality.
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spelling pubmed-63209822019-01-07 Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma Fianco, Giulia Contadini, Claudia Ferri, Alessandra Cirotti, Claudia Stagni, Venturina Barilà, Daniela Int J Mol Sci Review Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dependent phosphorylation of Caspase-8 on Tyr380. Loss of apoptotic signaling is a hallmark of cancer and indeed Caspase-8 expression is often lost in tumors. This event may account not only for cancer progression but also for cancer resistance to radiotherapy and chemotherapy. Intriguingly, other tumors, such as glioblastoma, preferentially retain Caspase-8 expression, and high levels of Caspase-8 expression may correlate with a worse prognosis, suggesting that in this context this protease loses its apoptotic activity and gains additional functions. Using different cellular systems, it has been clearly shown that in cancer Caspase-8 can exhibit non-canonical functions, including promotion of cell adhesion, migration, and DNA repair. Intriguingly, in glioblastoma models, Caspase-8 can promote NF-κB-dependent expression of several cytokines, angiogenesis, and in vitro and in vivo tumorigenesis. Overall, these observations suggest that some cancer cells may hijack Caspase-8 function which in turn promote cancer progression and resistance to therapy. Here we aim to highlight the multiple functions of Caspase-8 and to discuss whether the molecular mechanisms that modulate the balance between those functions may be targeted to dismantle the aberrant activity of Caspase-8 and to restore its canonical apoptotic functionality. MDPI 2018-11-29 /pmc/articles/PMC6320982/ /pubmed/30501030 http://dx.doi.org/10.3390/ijms19123798 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Fianco, Giulia
Contadini, Claudia
Ferri, Alessandra
Cirotti, Claudia
Stagni, Venturina
Barilà, Daniela
Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma
title Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma
title_full Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma
title_fullStr Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma
title_full_unstemmed Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma
title_short Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma
title_sort caspase-8: a novel target to overcome resistance to chemotherapy in glioblastoma
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320982/
https://www.ncbi.nlm.nih.gov/pubmed/30501030
http://dx.doi.org/10.3390/ijms19123798
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