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

1
Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy
2
Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(12), 3798; https://doi.org/10.3390/ijms19123798
Received: 8 November 2018 / Revised: 22 November 2018 / Accepted: 23 November 2018 / Published: 29 November 2018
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. View Full-Text
Keywords: Caspase-8; glioblastoma; FLIP; Src kinase; tyrosine phosphorylation; NF-κB; tumor microenvironment; chemotherapy and radiotherapy; DNA damage; apoptosis Caspase-8; glioblastoma; FLIP; Src kinase; tyrosine phosphorylation; NF-κB; tumor microenvironment; chemotherapy and radiotherapy; DNA damage; apoptosis
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Fianco, G.; Contadini, C.; Ferri, A.; Cirotti, C.; Stagni, V.; Barilà, D. Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma. Int. J. Mol. Sci. 2018, 19, 3798.

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