The interplay between SRC kinase and Caspase-8 phosphorylation on Y380 sustains the aberrant activation of NFkB signaling and promotes angiogenesis and resistance to therapy in glioblastoma

ABSTRACT: Caspase-8 is a cysteine protease that plays an essential role in apoptosis. Consistently with its canonical proapoptotic function, cancer cells may genetically or epigenetically downregulate its expression, or may dampen its enzymatic activity by promoting the expression of FLIP protein. However, unexpectedly, Caspase-8 expression is often retained in cancer even in the absence of FLIP up regulation, suggesting that alternative mechanisms may be exploited by cancer cells to cope with Caspase-8 expression. In this regard, we reported that SRC tyrosine kinase, which is aberrantly activated in many tumors, promotes Caspase-8 phosphorylation on Tyr380 and this event impairs Caspase-8 autoprocessing and full activation. Here, we investigated the significance of Caspase-8 expression in the modulation of gene expression in glioblastoma, a brain tumor where both Caspase-8 expression and SRC activity are often aberrantly upregulated. Transcriptomic analyses identified inflammatory response as a major target of Caspase-8 expression, and in particular, the NFkB signaling as one of the most affected pathways. More importantly, we could show that SRC kinase activity promotes Caspase-8 phosphorylation on Tyr380 in this context and that this event drives the assembly of a multiprotein complex that triggers NFkB activation, thereby inducing the expression of inflammatory and pro-angiogenetic factors. Moreover Caspase-8 phosphorylation on Tyr380 sustains neoangiogenesis and resistance to radiotherapy. In summary, our work identifies a novel interplay between SRC kinase and Caspase-8 that allows cancer cells to hijack Caspase-8 to sustain tumor growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193495 | GEO | 2022/12/29

REPOSITORIES: GEO