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.

Fianco, G., Contadini, C., Ferri, A., Cirotti, C., Stagni, V., Barila, D. (2018). Caspase-8: A novel target to overcome resistance to chemotherapy in glioblastoma. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 19(12), 3798 [10.3390/ijms19123798].

Caspase-8: A novel target to overcome resistance to chemotherapy in glioblastoma

Fianco G.;Cirotti C.;Barila D.
2018-01-01

Abstract

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.
2018
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/18 - GENETICA
English
Caspase-8; DNA damage; FLIP; NF-κB; Src kinase; apoptosis; chemotherapy and radiotherapy; glioblastoma; tumor microenvironment; tyrosine phosphorylation
Fianco, G., Contadini, C., Ferri, A., Cirotti, C., Stagni, V., Barila, D. (2018). Caspase-8: A novel target to overcome resistance to chemotherapy in glioblastoma. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 19(12), 3798 [10.3390/ijms19123798].
Fianco, G; Contadini, C; Ferri, A; Cirotti, C; Stagni, V; Barila, D
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/211987
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