Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma

Since inhibitor of apoptosis (IAP) proteins can regulate additional signaling pathways beyond apoptosis, we investigated the effect of the Smac mimetic BV6, which antagonizes IAP proteins, on non-apoptotic functions in glioblastoma (GBM). Here, we identify non-canonical NF-κB signaling and a TNFα/TNFR1 autocrine/paracrine loop as critical mediators of BV6-stimulated migration and invasion of GBM cells. In addition, BV6 triggers cell elongation, migration and invasion in primary, patient-derived GBM cells at non-toxic concentrations and also increase infiltrative tumor growth in vivo underscoring the relevance of…