Biologic sequelae of IκB kinase (IKK) inhibition in multiple myeloma: Therapeutic implications

60Citations
Citations of this article
28Readers
Mendeley users who have this article in their library.

Abstract

Nuclear factor-κB (NF-κB) has an important role in multiple myeloma (MM) cell pathogenesis in the context of the bone marrow (BM) microenvironment. In NF-κB signaling cascades, IκB kinase α (IKKα) and IKKβ are key molecules that predominantly mediate noncanonical and canonical pathways, respectively. In this study, we examined the biologic sequelae of the inhibition of IKKα versus IKKβ in MM cell lines. All MM cell lines have constitutive canonical NF-κB activity, and a subset of MM cell lines shows noncanonical NF-κB activity. Adhesion to BM stromal cells further activates both canonical and noncanonical NF-κB activity. IKKβ inhibitor MLN120B blocks canonical pathway and growth of MM cell lines but does not inhibit the noncanonical NF-κB pathway. Although IKKα knockdown induces significant growth inhibition in the cell lines with both canonical and noncanonical pathways, it does not inhibit NF-κB activation. Importantly, IKKα down-regulation decreases expression of β-catenin and aurora-A, which are known to mediate MMcell growth and survival. Finally, IKKβ inhibitor enhances the growth inhibition triggered by IKKα down-regulation in MM cells with both canonical and noncanonical NF-κB activity. Combination therapy targeting these kinases therefore represents a promising treatment strategy in MM. © 2009 by The American Society of Hematology.

Cite

CITATION STYLE

APA

Hideshima, T., Chauhan, D., Kiziltepe, T., Ikeda, H., Okawa, Y., Podar, K., … Anderson, K. C. (2009). Biologic sequelae of IκB kinase (IKK) inhibition in multiple myeloma: Therapeutic implications. Blood, 113(21), 5228–5236. https://doi.org/10.1182/blood-2008-06-161505

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free