Sphingosine 1-phosphate induces Mcl-1 upregulation and protects multiple myeloma cells against apoptosis.
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.
Li
Qing-Fang
QF
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, PR China.
Wu
Chu-Tse
CT
Guo
Qiang
Q
Wang
Hua
H
Wang
Li-Sheng
LS
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation
D008246:Lysophospholipids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D037342:Pertussis Toxin; D013110:Sphingosine