The new signaling pathway ERK5/TP53INP2 sensitizes cancer cells to death-receptor agonists and Natural Killer cells

The extrinsic apoptotic pathway is initiated by binding of TRAIL, TNFa or FasL to their cognate death receptors (DRs), leading to the intracellular assembly of the DISC complex and activation of caspase-8. Here, using 2D and 3D cell cultures and patient-derived xenograft organoids, we described a new signaling pathway that regulates activation of caspase-8 in response to DR agonists in cancer cells. Mechanistically, ERK5 phosphorylates and induces the ubiquitylation and proteasomal degradation of TP53INP2, a protein that mediates caspase-8 activation in response to DR agonists. Concordantly, ERK5 inhibition or genetic deletion induced TP53INP2 protein stabilization and sensitized cancer cells to DR agonists-induced extrinsic apoptosis, whereas ERK5 kinase activity protected cancer cells to apoptosis induced by DR agonists. Since TRAIL selectively induces apoptosis in cancer cells, our results support the use of ERK5 inhibitors as an effective strategy to sensitize cancer cells to TRAIL-based therapies, including Natural Killer cells expressing TRAIL.