title: Sphingosine 1-phosphate signaling through its receptor S1P5promotes chromosome segregation and mitotic progression.
abstract: Sphingosine kinase 1 (SphK1) promotes cell proliferation and survival, and its abundance is often increased in tumors. SphK1 produces the signaling lipid sphingosine 1-phosphate (S1P), which activates signaling cascades downstream five G protein-coupled receptors (S1P1-5) to modulate vascular and immune system function and promote proliferation. We identified a new function of the SphK1-S1P pathway specifically in the control of mitosis. SphK1 depletion in HeLa cells caused prometaphase arrest, whereas its overexpression or activation accelerated mitosis. Increasing the abundance of S1P promoted mitotic progression, overrode the spindle assembly checkpoint (SAC), and led to chromosome segregation defects. S1P was secreted through the transporter SPNS2 and stimulated mitosis by binding to and activating S1P5on the extracellular side, which then activated the intracellular phosphatidylinositol 3-kinase (PI3K)-AKT pathway. Knockdown of S1P5prevented the S1P-induced spindle defect phenotype. RNA interference assays revealed that the mitotic kinase Polo-like kinase 1 (PLK1) was an important effector of S1P-S1P5signaling-induced mitosis in HeLa cells. Our findings identify an extracellular signal and the downstream pathway that promotes mitotic progression and may indicate potential therapeutic targets to inhibit the proliferation of cancer cells.
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale, 31400 Toulouse, France.|Université de Toulouse, Université Paul Sabatier, 31400 Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, 31400 Toulouse, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Andrieu
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale, 31400 Toulouse, France.|Université de Toulouse, Université Paul Sabatier, 31400 Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, 31400 Toulouse, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Ledoux
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale, 31400 Toulouse, France.|Université de Toulouse, Université Paul Sabatier, 31400 Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, 31400 Toulouse, France.
authors.forename: Sophie
authors.identifier: http://orcid.org/0000-0002-5872-7363
authors.initials: S
authors.lastname: Branka
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale, 31400 Toulouse, France.|Université de Toulouse, Université Paul Sabatier, 31400 Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, 31400 Toulouse, France.
authors.forename: Magalie
authors.initials: M
authors.lastname: Bocquet
authors.affiliation: Clinical Trials Office, Biostatistics Unit, Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse-Oncopôle, 31100 Toulouse, France.
authors.forename: Julia
authors.identifier: http://orcid.org/0000-0002-0083-2582
authors.initials: J
authors.lastname: Gilhodes
authors.affiliation: INSERM U1111, 69635 Lyon, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Walzer
authors.affiliation: Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Kasahara
authors.affiliation: Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Inagaki
authors.affiliation: Lpath Inc., San Diego, CA 92121, USA.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Sabbadini
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale, 31400 Toulouse, France. olivier.cuvillier@inserm.fr anastassia.hatzoglou@ipbs.fr.|Université de Toulouse, Université Paul Sabatier, 31400 Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, 31400 Toulouse, France.
authors.forename: Olivier
authors.identifier: http://orcid.org/0000-0003-3346-375X
authors.initials: O
authors.lastname: Cuvillier
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale, 31400 Toulouse, France. olivier.cuvillier@inserm.fr anastassia.hatzoglou@ipbs.fr.|Université de Toulouse, Université Paul Sabatier, 31400 Toulouse, France.|Equipe Labellisée Ligue Contre le Cancer, 31400 Toulouse, France.
authors.forename: Anastassia
authors.identifier: http://orcid.org/0000-0001-7177-6808
authors.initials: A
authors.lastname: Hatzoglou
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D020090:Chromosome Segregation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008938:Mitosis / Q000187:drug effects*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D059008:Time-Lapse Imaging / Q000379:methods; D000097869:Polo-Like Kinase 1; D000099157:Sphingosine Kinase
chemical_list: D018797:Cell Cycle Proteins; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000097869:Polo-Like Kinase 1; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate