title: Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A.
abstract: The mechanisms by which sphingosine kinase-1 (SK-1)/sphingosine 1-phosphate (S1P) activation contributes to imatinib resistance in chronic myeloid leukemia (CML) are unknown. We show herein that increased SK-1/S1P enhances Bcr-Abl1 protein stability, through inhibition of its proteasomal degradation in imatinib-resistant K562/IMA-3 and LAMA-4/IMA human CML cells. In fact, Bcr-Abl1 stability was enhanced by ectopic SK-1 expression. Conversely, siRNA-mediated SK-1 knockdown in K562/IMA-3 cells, or its genetic loss in SK-1(-/-) MEFs, significantly reduced Bcr-Abl1 stability. Regulation of Bcr-Abl1 by SK-1/S1P was dependent on S1P receptor 2 (S1P2) signaling, which prevented Bcr-Abl1 dephosphorylation, and degradation via inhibition of PP2A. Molecular or pharmacologic interference with SK-1/S1P2 restored PP2A-dependent Bcr-Abl1 dephosphorylation, and enhanced imatinib- or nilotinib-induced growth inhibition in primary CD34(+) mononuclear cells obtained from chronic phase and blast crisis CML patients, K562/IMA-3 or LAMA4/IMA cells, and 32Dcl3 murine progenitor cells, expressing the wild-type or mutant (Y253H or T315I) Bcr-Abl1 in situ. Accordingly, impaired SK-1/S1P2 signaling enhanced the growth-inhibitory effects of nilotinib against 32D/T315I-Bcr-Abl1-derived mouse allografts. Since SK-1/S1P/S1P2 signaling regulates Bcr-Abl1 stability via modulation of PP2A, inhibition of SK-1/S1P2 axis represents a novel approach to target wild-type- or mutant-Bcr-Abl1 thereby overcoming drug resistance.
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Arelis
authors.initials: A
authors.lastname: Salas
authors.forename: Suriyan
authors.initials: S
authors.lastname: Ponnusamy
authors.forename: Can E
authors.initials: CE
authors.lastname: Senkal
authors.forename: Marisa
authors.initials: M
authors.lastname: Meyers-Needham
authors.forename: Shanmugam Panneer
authors.initials: SP
authors.lastname: Selvam
authors.forename: Sahar A
authors.initials: SA
authors.lastname: Saddoughi
authors.forename: Elif
authors.initials: E
authors.lastname: Apohan
authors.forename: R David
authors.initials: RD
authors.lastname: Sentelle
authors.forename: Charles
authors.initials: C
authors.lastname: Smith
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gault
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.forename: Hesham M
authors.initials: HM
authors.lastname: El-Shewy
authors.forename: Joshua
authors.initials: J
authors.lastname: Oaks
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Baran
authors.forename: Sandeep
authors.initials: S
authors.lastname: Mahajan
authors.forename: Daniel
authors.initials: D
authors.lastname: Fernandes
authors.forename: Robert
authors.initials: R
authors.lastname: Stuart
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Besim
authors.initials: B
authors.lastname: Ogretmen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D054875:Ubiquitination; D000099157:Sphingosine Kinase
chemical_list: D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D010879:Piperazines; D054648:Protein Phosphatase 2; D011743:Pyrimidines; D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C498826:nilotinib