NEDDylation is required for CRLs to be active; however, using the NEDDylation inhibitor MLN4924, we found that TRAIL-induced apoptosis was enhanced rather than suppressed in cancer cells co-treated with MLN4924 and TRAIL, suggesting an alternative NEDDylation-dependent modulator of TRAIL-R2 apoptotic signalling. This evidence concerns the gene TNFSF10 and cancer.