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.

Hyaluronan is required for cranial neural crest cells migration and craniofacial development

“…This result is in line with the analysis of the CD44 null mutant mice, which, surprisingly, do not reveal major developmental defects (Protin et al, 1999). Although previous studies have demonstrated that in in vitro cellular systems hyaluronan provides cells with apoptotic protection via the interaction with hyaluronan receptor CD44 (Kaneko et al, 2000;Ozeki et al, 2001;Ohwada et al, 2008), our findings seem to point out that in a more complex in vivo system, other hyaluronan receptors might compensate for CD44 depletion (Nedvetzki et al, 2004). In this respect, it is important to note that RHAMM, another hyaluronan receptor, is expressed in cranial NCC during Xenopus development (Casini et al, 2010).…”

Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance

“…The expression of these class of markers has been shown to be intrinsically related to different PC chemoresistant potential in vitro and in vivo, [40][41][42][43][44][45] as well as to patients' survival, [46][47][48] which would be potentially due to a stronger attachment of MRD clonal PCs to the BM stroma, which provides higher protection from 49,50 In fact, it could be hypothesized that a subset of chemoresistant MRD cells strongly attached to the stroma might be potentially underestimated in BM aspirates. By contrast, a different role has been assigned to CD44 in cell adhesion-mediated drug resistance in several cancers including MM, where CD44 may partially contribute to dexamethasone resistance 51 and becomes upregulated in lenalidomide-resistant MM cells to stabilize the expression of P-glycoprotein, a multidrug resistance efflux pump responsible for the cellular uptake of lenalidomide. 13,52 Interestingly, differences between diagnostic vs MRD cells were more pronounced among patients treated only with VMP vs cases exposed to VMP and Rd.…”

CD44 in hematological neoplasias

“…Similarly in MM, treatment success of Dexamethasone was dependent on CD44 with decreased apoptosis rates in cells with high CD44 [148]. Here neutralizing CD44 might reveal new therapeutic strategies in treatment of multidrug resistant haematological malignancies.…”