title: Toll-like receptor (TLR)-1/2 triggering of multiple myeloma cells modulates their adhesion to bone marrow stromal cells and enhances bortezomib-induced apoptosis.
abstract: In multiple myeloma (MM), the malignant plasma cells usually localize to the bone marrow where they develop drug resistance due to adhesion to stromal cells and various environmental signals. Hence, modulation of this interaction is expected to influence drug sensitivity of MM cells. Toll-like receptor (TLR) ligands have displayed heterogeneous effects on B-cell malignancies and also on MM cells in a few recent studies, but effects on adhesion and drug sensitivity of myeloma cells in the context of bone marrow stromal cells (BMSCs) have never been investigated. In the present study, we explored the modulatory effects of TLR1/2 ligand (Pam3CSK4) on adhesion of human myeloma cells to BMSCs. It is shown that TLR1/2 triggering has opposite effects in different HMCLs on their adhesion to BMSCs. Fravel, L363, UM-6, UM-9 and U266 showed increased adhesion to BMSC in parallel with an increased surface expression of integrin molecules α4 and αVβ3. OPM-1, OPM-2 and NCI-H929 showed a dose-dependent decrease in adhesion upon TLR activation following a downregulation of β7 integrin expression. Importantly, TLR1/2 triggering increased cytotoxic and apoptotic effects of bortezomib in myeloma cells independent of the effect on stromal cell adhesion. Moreover, the apoptosis-enhancing effect of Pam3CSK4 paralleled induction of cleaved caspase-3 protein in FACS analysis suggesting a caspase-dependent mechanism. Our findings uncover a novel role of TLR activation in MM cells in the context of bone marrow microenvironment. Stimulation of TLR1/2 bypasses the protective shield of BMSCs and may be an interesting strategy to enhance drug sensitivity of multiple myeloma cells.
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Abdi
authors.affiliation: Department of Clinical Chemistry & Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Tuna
authors.initials: T
authors.lastname: Mutis
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Garssen
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Redegeld
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D016023:Integrins / Q000276:immunology; D055666:Lipopeptides / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology; D011719:Pyrazines / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects / Q000276:immunology; D051194:Toll-Like Receptor 1 / Q000819:agonists / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016023:Integrins; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D011719:Pyrazines; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D000069286:Bortezomib