title: Critical role of Spns2, a sphingosine-1-phosphate transporter, in lung cancer cell survival and migration.
abstract: The sphingosine-1-phosphate (S1P) transporter Spns2 regulates myocardial precursor migration in zebrafish and lymphocyte trafficking in mice. However, its function in cancer has not been investigated. We show here that ectopic Spns2 expression induced apoptosis and its knockdown enhanced cell migration in non-small cell lung cancer (NSCLC) cells. Metabolically, Spns2 expression increased the extracellular S1P level while its knockdown the intracellular. Pharmacological inhibition of S1P synthesis abolished the augmented cell migration mediated by Spns2 knockdown, indicating that intracellular S1P plays a key role in this process. Cell signaling studies indicated that Spns2 expression impaired GSK-3β and Stat3 mediated pro-survival pathways. Conversely, these pathways were activated by Spns2 knockdown, which explains the increased cell migration since they are also crucial for migration. Alterations of Spns2 were found to affect several enzymes involved in S1P metabolism, including sphingosine kinases, S1P phosphatases, and S1P lyase 1. Genetically, Spns2 mRNA level was found to be reduced in advanced lung cancer (LC) patients as quantified by using a small scale qPCR array. These data show for the first time that Spns2 plays key roles in regulating the cellular functions in NSCLC cells, and that its down-regulation is a potential risk factor for LC.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Bradley
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Somsankar
authors.initials: S
authors.lastname: Dasgupta
authors.affiliation: Shengjing Hospital, China Medical University, Shenyang, Liaoning, P.R. China.
authors.forename: Xue
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Xiaying
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Gu
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Qian
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Dinkins
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Erhard
authors.initials: E
authors.lastname: Bieberich
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Guanghu
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001692:Biological Transport; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D008246:Lysophospholipids; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; C000598727:Spns2 protein, human; C060506:sphingosine 1-phosphate; D013110:Sphingosine