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

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 metabolism. mTORC1 activity results in p62 phosphorylation allowing its dependent sequestration of KEAP1 protein and constitutive NRF2 signaling activation, as a consequence. Overall, this work depicted a novel unexpected role for Caspase-8 in the modulation of cancer cell metabolism, bridging together Src, mTORC1 and NRF2 signaling.