Biologic sequelae of I{kappa}B kinase (IKK) inhibition in multiple myeloma: therapeutic implications

Nuclear factor-kappaB (NF-kappaB) has an important role in multiple myeloma (MM) cell pathogenesis in the context of the bone marrow (BM) microenvironment. In NF-kappaB signaling cascades, IkappaB kinase alpha (IKKalpha) and IKKbeta are key molecules that predominantly mediate noncanonical and canonical pathways, respectively. In this study, we examined the biologic sequelae of the inhibition of IKKalpha versus IKKbeta in MM cell lines. All MM cell lines have constitutive canonical NF-kappaB activity, and a subset of MM cell lines shows noncanonical NF-kappaB activity. Adhesion to BM stromal cells further activates both canonical and noncanonical NF-kappaB activity. IKKbeta inhibitor MLN120B blocks canonical pathway and growth of MM cell lines but does not inhibit the noncanonical NF-kappaB pathway. Although IKKalpha knockdown induces significant growth inhibition in the cell lines with both canonical and noncanonical pathways, it does not inhibit NF-kappaB activation. Importantly, IKKalpha down-regulation decreases expression of beta-catenin and aurora-A, which are known to mediate MM cell growth and survival. Finally, IKKbeta inhibitor enhances the growth inhibition triggered by IKKalpha down-regulation in MM cells with both canonical and noncanonical NF-kappaB activity. Combination therapy targeting these kinases therefore represents a promising treatment strategy in MM.