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

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.

Keywords: Caspase-8; DNA damage; FLIP; NF-κB; Src kinase; apoptosis; chemotherapy and radiotherapy; glioblastoma; tumor microenvironment; tyrosine phosphorylation.

Figure 1

Src kinase-dependent phosphorylation on Tyr380 rewires Caspase-8 functionality in cancer cells. Phosphorylation on Tyr380 (P-Y380) impairs the apoptotic function of Caspase-8 and promotes its ability to sustain cell adhesion and migration, neoplastic transformation and to impair anoikis. Arrows indicate induction and T-bar indicates inhibition.

Figure 2

Role of Caspase-8 in cancer therapy. Caspase-8 may modulate the response to therapeutic approaches through canonical and non-canonical functions. Chemotherapy and radiotherapy promote DNA damage that in turn switches-on the enzymatic activation of Caspase-8, either directly or via the ATM-dependent downregulation of FLIP protein levels. Caspase-8 enzymatic activation promotes apoptosis therefore enhancing cancer cell sensitivity to chemotherapy and TRAIL. Cancer cells may rewire Caspase-8 functionality; in these contexts, Caspase-8 can promote NF-κB activity, cytokine production and DNA repair, therefore promoting resistance to chemotherapy. Overall, we suggest that this dual role of Caspase-8 in cancer may be exploited to ameliorate cancer therapy. Blue arrows for canonical pathway; green arrows for non canonical pathway.