4.7 Article

Inverse signaling of the transmembrane chemokine CXCL16 contributes to proliferative and anti-apoptotic effects in cultured human meningioma cells

Journal

CELL COMMUNICATION AND SIGNALING
Volume 14, Issue -, Pages -

Publisher

BIOMED CENTRAL LTD
DOI: 10.1186/s12964-016-0149-7

Keywords

Chemokines; Chemokine receptors; Cellular communication; Meningioma; Inverse signaling

Categories

Funding

  1. University of Kiel
  2. Deutsche Forschungsgemeinschaft [HE 3400/5-1, ME 758/10-1]
  3. German Ministry for Education and Research [01EY1103]
  4. popgen 2.0 network [(P2N)]

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Background: 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. Methods: 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. Results: 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. Conclusion: 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.

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