title: CD44 and hyaluronan engagement promotes dexamethasone resistance in human myeloma cells.
abstract: Dexamethasone (Dex) is an effective therapeutic agent against multiple myeloma (MM); however, resistance to it often becomes a clinical issue. CD44 is an adhesion molecule that serves as a cell surface receptor for extracellular matrix components, including hyaluronan (HA). HA is an extracellular matrix component that is involved in survival and progression in MM. In the present report, we describe isolation of a CD44-expressing population from a Dex-sensitive MM cell line, RPMI8226, in which the CD44-high population had a significantly higher potential to resist Dex than did the CD44-low population. Furthermore, we demonstrate that CD44 engagement by an anti-CD44 monoclonal antibody (mAb) or HA protects MM cells from Dex-induced growth inhibition. The activity of HA was partially inhibited by blocking its binding to CD44, indicating that CD44 mediates HA activity promoting MM cell survival. CD44 engagement by an anti-CD44 mAb led to phosphorylation and degradation of IkappaB-alpha, thus preventing its Dex-induced up-regulation. Our data suggest that CD44 is not only an important mediator for the survival activity of HA, but it may also contribute to MM cell resistance to Dex.
authors: Division of Hematology, Department of Clinical Cell Biology, Chiba University Graduate School of Medicine, Chiba City, Chiba, Japan.
authors: Chikako
authors: C
authors: Ohwada
authors: Chiaki
authors: C
authors: Nakaseko
authors: Masayuki
authors: M
authors: Koizumi
authors: Masahiro
authors: M
authors: Takeuchi
authors: Shinichi
authors: S
authors: Ozawa
authors: Megumi
authors: M
authors: Naito
authors: Hiroaki
authors: H
authors: Tanaka
authors: Kayo
authors: K
authors: Oda
authors: Ryuko
authors: R
authors: Cho
authors: Miki
authors: M
authors: Nishimura
authors: Yasushi
authors: Y
authors: Saito
mesh_terms: D000911:Antibodies, Monoclonal / Q000502:physiology; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism* / Q000502:physiology; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C497483:CD44 protein, human; D006131:Growth Inhibitors; D018960:Hyaluronan Receptors; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D003907:Dexamethasone; D006820:Hyaluronic Acid