title: The Sphingosine-1-Phosphate Modulator FTY720 Targets Multiple Myeloma via the CXCR4/CXCL12 Pathway.
abstract: Purpose:To explore the functional consequences of possible cross-talk between the CXCR4/CXCL12 and the sphingosine-1-phosphate (S1P) pathways in multiple myeloma (MM) cells and to evaluate the effect of S1P targeting with the FTY720 modulator as a potential anti-MM therapeutic strategy.Experimental Design and Results:S1P targeting with FTY720 induces MM cell apoptosis. The combination of FTY720 with the SPHK1 inhibitor SKI-II results in synergistic inhibition of MM growth. CXCR4/CXCL12-enhanced expression correlates with reduced MM cell sensitivity to both FTY720 and SKI-II inhibitors, and with SPHK1 coexpression in both cell lines and primary MM bone marrow (BM) samples, suggesting regulative cross-talk between the CXCR4/CXCL12 and SPHK1 pathways in MM cells. FTY720 was found to directly target CXCR4. FTY720 profoundly reduces CXCR4 cell-surface levels and abrogates the CXCR4-mediated functions of migration toward CXCL12 and signaling pathway activation. Moreover, FTY720 cooperates with bortezomib, inducing its cytotoxic activity and abrogating the bortezomib-mediated increase in CXCR4 expression. FTY720 effectively targets bortezomib-resistant cells and increases their sensitivity to bortezomib, promoting DNA damage. Finally, in a recently developed novel xenograft model of CXCR4-dependent systemic MM with BM involvement, FTY720 treatment effectively reduces tumor burden in the BM of MM-bearing mice. FTY720 in combination with bortezomib demonstrates superior tumor growth inhibition and abrogates bortezomib-induced CXCR4 increase on MM cells.Conclusions:Altogether, our work identifies a cross-talk between the S1P and CXCR4 pathways in MM cells and provides a preclinical rationale for the therapeutic application of FTY720 in combination with bortezomib in patients with MM.Clin Cancer Res; 23(7); 1733-47. ©2016 AACR.
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Katia
authors.initials: K
authors.lastname: Beider
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Rosenberg
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bitner
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Avichai
authors.initials: A
authors.lastname: Shimoni
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Merav
authors.initials: M
authors.lastname: Leiba
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Koren-Michowitz
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Ribakovsky
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Shiri
authors.initials: S
authors.lastname: Klein
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Devorah
authors.initials: D
authors.lastname: Olam
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Lola
authors.initials: L
authors.lastname: Weiss
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Wald
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Abraham
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Amnon
authors.initials: A
authors.lastname: Peled
authors.affiliation: Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel. a.nagler@sheba.health.gov.il.
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000008:administration & dosage; D054377:Chemokine CXCL12 / Q000235:genetics*; D004249:DNA Damage / Q000187:drug effects; D004357:Drug Synergism; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
chemical_list: D000069286:Bortezomib; D054377:Chemokine CXCL12; D000068876:Fingolimod Hydrochloride; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D019718:Receptors, CXCR4; D013110:Sphingosine; D000099157:Sphingosine Kinase; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C060506:sphingosine 1-phosphate