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Blood, 21 May 2009, Vol. 113, No. 21, pp. 5228-5236.
Prepublished online as a Blood First Edition Paper on March 6, 2009; DOI 10.1182/blood-2008-06-161505.
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LYMPHOID NEOPLASIA
Biologic sequelae of I B kinase (IKK) inhibition in multiple myeloma: therapeutic implications
Teru Hideshima1,
Dharminder Chauhan1,
Tanyel Kiziltepe1,
Hiroshi Ikeda1,
Yutaka Okawa1,
Klaus Podar1,
Noopur Raje1,
Alexei Protopopov1,
Nikhil C. Munshi1,
Paul G. Richardson1,
Ruben D. Carrasco1, and
Kenneth C. Anderson1
1 Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Nuclear factor- B (NF-B) has an important role in multiple myeloma (MM) cell pathogenesis in the context of the bone marrow (BM) microenvironment. In NF-B signaling cascades, IB kinase  (IKK) 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 IKK versus IKKβ in MM cell lines. All MM cell lines have constitutive canonical NF-B activity, and a subset of MM cell lines shows noncanonical NF-B activity. Adhesion to BM stromal cells further activates both canonical and noncanonical NF-B activity. IKKβ inhibitor MLN120B blocks canonical pathway and growth of MM cell lines but does not inhibit the noncanonical NF-B pathway. Although IKK knockdown induces significant growth inhibition in the cell lines with both canonical and noncanonical pathways, it does not inhibit NF-B activation. Importantly, IKK down-regulation decreases expression of β-catenin and aurora-A, which are known to mediate MM cell growth and survival. Finally, IKKβ inhibitor enhances the growth inhibition triggered by IKK down-regulation in MM cells with both canonical and noncanonical NF-B activity. Combination therapy targeting these kinases therefore represents a promising treatment strategy in MM.
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