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.

The role of caspase-8 in the tumor microenvironment of ovarian cancer

“…The functions of caspase-8 are tightly modulated by cFLIP proteins, XIAP, and posttranslational modifications such as phosphorylation and ubiquitination. However, the significance of these mechanisms to regulate caspase-8 in cancers has to be further investigated [91].…”

“…In contrast, caspase-8 expression increases in glioblastoma, promoting sustained NFκB activation and the transcription of several cytokines. The levels of IL-8, IL-6, IL1β, CCL2, and VEGF correlate with caspase-8 expression levels, thereby painting caspase-8 as a modulator of angiogenesis and inflammation in glioblastoma [91,92].…”

<p>Polyphyllin VI Induces Apoptosis and Autophagy via Reactive Oxygen Species Mediated JNK and P38 Activation in Glioma</p>

“…27,28 The exogenous apoptosis pathway is initiated by Caspase-8, with its activation leading to subsequent downstream cascade reactions. 29 In the intrinsic pathway, cells triggered by intracellular stimuli through the Bcl-2 protein family activate caspase-9 and caspase-3. 30,31 In the present study, PPVI induced apoptosis in osteosarcoma cells by activating apoptosis pathways.…”

SRC Kinase in Glioblastoma: News from an Old Acquaintance

“…In addition, we recently observed that caspase-8 expression in GBM played a non-canonical function sustaining NF-κB activation, cytokine production (i.e., IL-6, IL-8, IL-1β, MCP-1, and VEGF-α), and tumor growth in vivo [ 33 , 48 ]. Importantly, we have also reported that the aberrant activation of SRC in GBM cell lines promoted caspase-8 phosphorylation on Y380, leading to neoplastic transformation [ 49 ].…”