Caspase-8 expression and its Src dependent phosphorylation on Tyrosine 380 triggers NRF2 signaling activation in glioblastoma.

ABSTRACT: Caspase-8 expression is upregulated in many tumors where, despite its canonical apoptotic pathway, it sustains cancer progression promoting cell migration, NF-kB activation and inflammation. Here, we provide the first evidence for a novel role of Caspase-8 in promoting the metabolic rewiring of cancer cells. By performing transcriptomic, proteomic and phosphoproteomic analyses on glioblastoma cellular models, we identify Caspase-8 as an unexpected modulator of NRF2. Here we show that Caspase-8 expression and phosphorylation affect NRF2 activity and mitochondrial homeostasis. Mechanistically, we demonstrate that Src-dependent phosphorylation of Caspase-8 on Tyrosine 380 (Y380), frequently reported in cancers including glioblastoma, sustains mTORC1 activation, thus promoting energy metabolis

SUBMITTER: Cirotti C 

PROVIDER: S-EPMC12669649 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature