sphingosine-1-phosphate and Multiple-Myeloma

In this chapter, we review the latest developments concerning the role of sphingosine 1-phosphate (S1P) in cancer. Particular focus is paid to the role of sphingosine kinases 1 and 2, S1P lyase and S1P-dependent signalling networks in both solid tumours and haematological cancer. The potential of this S1P-dependent pathophysiology as a therapeutic target for the treatment of cancer is also discussed.

Topics: Aldehyde-Lyases; Animals; Antineoplastic Agents; Humans; Leukemia, Myeloid; Lysophospholipids; Molecular Targeted Therapy; Multiple Myeloma; Neoplasms; Oncogenes; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine

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.

Topics: Animals; Bone Marrow; Cell Adhesion; Cell Shape; Chemokine CXCL12; Coculture Techniques; GTPase-Activating Proteins; Guanine Nucleotide Exchange Factors; Humans; Integrin alpha4beta1; Integrin alpha5beta1; K562 Cells; Lysophospholipids; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; rac1 GTP-Binding Protein; Receptors, Lysosphingolipid; RNA Interference; Signal Transduction; Sphingosine; Stromal Cells; Talin; Time Factors; Transendothelial and Transepithelial Migration; Transfection; Tumor Cells, Cultured; Vascular Cell Adhesion Molecule-1

Fenretinide (4HPR), a nontoxic analog of ATRA, has been investigated in various malignancies but not in multiple myeloma (MM), a plasma cell malignancy associated with induction of osteolytic bone disease. Here we show that 4HPR induces apoptosis through increased level of ROS and activation of caspase-8, 9 and 3, and inhibits growth of several MM cell lines in a dose-dependent manner. Serum or co-culture with the supportive osteoclasts partially protects MM cells from 4HPR-induced growth inhibition. Sphingosine-1 phosphate (S1P) significantly protects MM cells from 4HPR-induced apoptosis suggesting that as in other malignancies, this drug up-regulates ceramide in MM cells. 4HPR has no toxic effects on non-malignant cells such as blood mononucleated cells, mesenchymal stem cells and osteoblasts, but markedly reduces viability of endothelial cells and mature osteoclasts and inhibits differentiation of osteoclasts and MM-induced tube formation. 4HPR is a potential anti-MM agent, affecting MM cells and MM-induced bone disease and angiogenesis.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Apoptosis; Caspases; Cell Differentiation; Cells, Cultured; Coculture Techniques; Drug Screening Assays, Antitumor; Endothelial Cells; Enzyme Activation; Fenretinide; Humans; Leukocytes, Mononuclear; Lysophospholipids; Multiple Myeloma; Neoplasm Proteins; Neovascularization, Pathologic; Organoids; Osteoblasts; Osteoclasts; Reactive Oxygen Species; Sphingosine; Tumor Cells, Cultured

Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid which is known to induce diverse cellular responses through at least five G-protein-coupled receptors on various cell types. However, neither the distribution of S1P receptors nor the effects of S1P on multiple myeloma (MM) cells are fully understood. Here, we show that MM cells express the S1P receptors, S1P1, S1P2, and S1P3. Furthermore, S1P protects MM cells against Dex-induced apoptosis. Importantly, S1P upregulates Mcl-1 expression in a time- and concentration-dependent manner in human MM cell lines. Treatment of MM cells with pertussis toxin (PTX), a pan-S1P receptor inhibitor, results in blockage of S1P-induced upregulation of Mcl-1. These data demonstrate that S1P upregulates the expression of Mcl-1 and protects MM cells from Dex-induced apoptosis, providing the preclinical framework for novel therapeutics targeting at both Mcl-1 and/or S1P to improve the patient outcome in MM.

Topics: Apoptosis; Cell Line, Tumor; Humans; Lysophospholipids; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Pertussis Toxin; Proto-Oncogene Proteins c-bcl-2; Receptors, Lysosphingolipid; Sphingosine; Up-Regulation