title: "Inverse signaling" of the transmembrane chemokine CXCL16 contributes to proliferative and anti-apoptotic effects in cultured human meningioma cells.
abstract: Chemokines and their receptors play a decisive role in tumor progression and metastasis. We recently found a new signaling mechanism in malignant glioma cells mediated by transmembrane chemokines that we termed "inverse signaling". According to this hypothesis, soluble (s)-CXCL16 binds to the surface-expressed transmembrane (tm) -CXCL16, and induces signaling and different biological effects in the stimulated cells, so that the transmembrane ligand itself acts as a receptor for its soluble counterpart. Now, we hypothesized that "inverse signaling" via tm-CXCL16 might also take place in meningiomas, a completely different, benign tumor entity.
  
  
  
  We used quantitative reverse-transcription polymerase chain reaction, immunocytochemistry and western blot to detect CXCL16 and CXCR6 in human meningioma cells isolated from 28 human meningiomas. Subsequently, we stimulated cultured human tm-CXCL16-positive, CXCR6-negative meningioma cells with recombinant s-CXCL16 and analyzed binding, signaling and biological effects using RNAi silencing to verify specificity.
  
  
  
  In fact, cultured human meningioma cells considerably express CXCL16, but substantially lack CXCR6, the only known CXCL16 receptor. These receptor-negative cells could bind s-CXCL16, and responded to s-CXCL16 application with activation of the intracellular kinases ERK1/2 und Akt. As a consequence, we observed increased proliferation and rescue of apoptosis of cultured meningioma cells. Since binding and signaling were abolished by siRNA silencing, we concluded that tm-CXCL16 specifically acts as a receptor for s-CXCL16 also in human meningioma cells.
  
  
  
  These findings underline our recent report on the mechanism of inverse signaling as a broad biological process also observable in more benign tumor cells and contributing to tumor progression.
authors: Department of Anatomy, University of Kiel, Otto-Hahn-Place 8, 24118, Kiel, Germany.
authors: Kirsten
authors: K
authors: Hattermann
authors: Department of Neurosurgery, University of Schleswig-Holstein Medical Center, Campus Kiel, Arnold-Heller-Str.3, Building 41, 24105, Kiel, Germany.
authors: Kareen
authors: K
authors: Bartsch
authors: Department of Anatomy, University of Kiel, Otto-Hahn-Place 8, 24118, Kiel, Germany.
authors: Henrike H
authors: HH
authors: Gebhardt
authors: Department of Neurosurgery, University of Schleswig-Holstein Medical Center, Campus Kiel, Arnold-Heller-Str.3, Building 41, 24105, Kiel, Germany.
authors: H Maximilian
authors: HM
authors: Mehdorn
authors: Department of Neurosurgery, University of Schleswig-Holstein Medical Center, Campus Kiel, Arnold-Heller-Str.3, Building 41, 24105, Kiel, Germany.
authors: Michael
authors: M
authors: Synowitz
authors: Department of Neurosurgery, University of Schleswig-Holstein Medical Center, Campus Kiel, Arnold-Heller-Str.3, Building 41, 24105, Kiel, Germany.
authors: Anne Dorothée
authors: AD
authors: Schmitt
authors: Department of Anatomy, University of Kiel, Otto-Hahn-Place 8, 24118, Kiel, Germany.
authors: Rolf
authors: R
authors: Mentlein
authors: Department of Neurosurgery, University of Schleswig-Holstein Medical Center, Campus Kiel, Arnold-Heller-Str.3, Building 41, 24105, Kiel, Germany. janka.held-feindt@uksh.de.
authors: Janka
authors: J
authors: Held-Feindt
mesh_terms: D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008577:Meningeal Neoplasms / Q000378:metabolism*; D008579:Meningioma / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051116:Receptors, Scavenger / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C423727:CXCL16 protein, human; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D051116:Receptors, Scavenger; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Cellular communication; Chemokine receptors; Chemokines; Inverse signaling; Meningioma