Possible mechanism whereby bortezomib triggers canonical NF-κB activation. Bortezomib either directly or indirectly (via RIP2) activates IKKβ, which subsequently phosphorylates IκBα, an inhibitor of p50/p65. After nonproteasomal degradation of IκBα, p50/p65 translocates to nucleus. IKKβ inhibitors block down-regulation of IκBα and NF-κB activity as well as enhance bortezomib-induced cytotoxicity. See the complete figure in the article beginning on page 1046.