CD44 and hyaluronan engagement promotes dexamethasone resistance in human myeloma cells.
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.
Ohwada
Chikako
C
Division of Hematology, Department of Clinical Cell Biology, Chiba University Graduate School of Medicine, Chiba City, Chiba, Japan.
Nakaseko
Chiaki
C
Koizumi
Masayuki
M
Takeuchi
Masahiro
M
Ozawa
Shinichi
S
Naito
Megumi
M
Tanaka
Hiroaki
H
Oda
Kayo
K
Cho
Ryuko
R
Nishimura
Miki
M
Saito
Yasushi
Y
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
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