Submitted June 4, 2008
Accepted February 28, 2009
Biologic sequelae of I
B kinase (IKK) inhibition in multiple myeloma: therapeutic implications
Teru Hideshima, Dharminder Chauhan, Tanyel Kiziltepe, Hiroshi Ikeda, Yutaka Okawa, Klaus Podar, Noopur Raje, Alexei Protopopov, Nikhil C. Munshi, Paul G. Richardson, Ruben D. Carrasco, and Kenneth C. Anderson*
Jerome Lipper Multiple Myeloma Center, Department of Medical oncology, Dana-Farber Cancer Institute, Boston, MA, United States
* Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu.
NF-
B has an important role in multiple myeloma (MM) cell pathogenesis in the context of the bone marrow (BM) microenvironment. In NFB signaling cascades, IB kinase (IKK)
and IKK
are key molecules which predominantly mediate non-canonical and canonical pathways, respectively. In this study, we examined the biologic sequelae of the inhibition of IKK versus IKK in MM cell lines. All MM cell lines have constitutive canonical NF-B activity and a subset of MM cell lines show non-canonical NF-B activity. Adhesion to BM stromal cells further activates both canonical and non-canonical NF-B activity. IKK inhibitor MLN120B blocks canonical pathway and growth of MM cell lines, but does not inhibit non-canonical NF-B pathway. Although IKK knockdown induces significant growth inhibition in the cell lines with both canonical and non-canonical pathways, it does not inhibit NF-B activation. Importantly, IKK downregulation decreases expression of -catenin and aurora-A, which are known to mediate MM cell growth and survival. Finally, IKK inhibitor enhances the growth inhibition triggered by IKK downregulation in MM cells with both canonical and non-canonical NF-B activity. Combination therapy targeting these kinases therefore represents a promising treatment strategy in MM.
