Sphingosine-1-phosphate activates chemokine-promoted myeloma cell adhesion and migration involving α4β1 integrin function.
Myeloma cell adhesion dependent on α4β1 integrin is crucial for the progression of multiple myeloma (MM). The α4β1-dependent myeloma cell adhesion is up-regulated by the chemokine CXCL12, and pharmacological blockade of the CXCL12 receptor CXCR4 leads to defective myeloma cell homing to bone marrow (BM). Sphingosine-1-phosphate (S1P) regulates immune cell trafficking upon binding to G-protein-coupled receptors. Here we show that myeloma cells express S1P1, a receptor for S1P. We found that S1P up-regulated the α4β1-mediated myeloma cell adhesion and transendothelial migration stimulated by CXCL12. S1P promoted generation of high-affinity α4β1 that efficiently bound the α4β1 ligand VCAM-1, a finding that was associated with S1P-triggered increase in talin-β1 integrin association. Furthermore, S1P cooperated with CXCL12 for enhancement of α4β1-dependent adhesion strengthening and spreading. CXCL12 and S1P activated the DOCK2-Rac1 pathway, which was required for stimulation of myeloma cell adhesion involving α4β1. Moreover, in vivo analyses indicated that S1P contributes to optimizing the interactions of MM cells with the BM microvasculture and for their lodging inside the bone marrow. The regulation of α4β1-dependent adhesion and migration of myeloma cells by CXCL12-S1P combined activities might have important consequences for myeloma disease progression.
Cellular and Molecular Medicine Programme, Centro de Investigaciones Biológicas, Madrid, Spain.
David
D
García-Bernal
Javier
J
Redondo-Muñoz
Ana
A
Dios-Esponera
Raphaël
R
Chèvre
Elvira
E
Bailón
Mercedes
M
Garayoa
Nohemí
N
Arellano-Sánchez
Norma C
NC
Gutierrez
Andrés
A
Hidalgo
Angeles
A
García-Pardo
Joaquin
J
Teixidó
D000818:Animals; D001853:Bone Marrow / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D048430:Cell Shape; D054377:Chemokine CXCL12 / Q000378:metabolism*; D018920:Coculture Techniques; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000378:metabolism; D020014:K562 Cells; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016608:Talin / Q000378:metabolism; D013997:Time Factors; D057705:Transendothelial and Transepithelial Migration; D014162:Transfection; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D054377:Chemokine CXCL12; C402110:DOCK2 protein, human; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D008246:Lysophospholipids; C107953:RAC1 protein, human; D049349:Receptors, Lysosphingolipid; C518832:TLN1 protein, human; D016608:Talin; D019010:Vascular Cell Adhesion Molecule-1; C060506:sphingosine 1-phosphate; D020830:rac1 GTP-Binding Protein; D013110:Sphingosine