Abstract
Abstract Switches in the sphingolipid metabolism have recently been associated with oncogenic transformation, and a role for the low density lipoprotein receptor related protein (LRP1) in the sphingosine-1-phosphate (S1P) proangiogenic signalling inferred. Although S1P is a key determinant of blood-brain barrier (BBB) permeability, the interdependent signalling crosstalk with LRP1 in brain endothelial cells (EC) remains unclear. Here, we tested whether any adaptive LRP1/S1P interdependence mechanisms are required in a SV40-immortalized human brain microvascular EC (HBMEC) model which closely mimics the brain tumor endothelium phenotype. Transient LRP1 silencing and stable LRP1-/- HBMEC were generated and increased expression of CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor which regulates the transcription of all five S1P receptors members, was observed upon stable but not transient LRP1 repression. Migration of EC isolated from Lrp1(EC)-/- mice and of stable LRP1-/- HBMEC became unresponsive to S1P, in part explained by altered ERK and p38 MAPK pathways, whereas it remained unaltered in transient in vitro LRP1 repression. Adaptive diminished expressions of S1P1, S1P3, and S1P5, and increased S1P2 were observed in stable LRP1-/- HBMEC and in brain EC isolated from Lrp1(EC)-/- mice. Finally, gene silencing strategies highlighted the need for S1P3 for proper S1P-mediated HBMEC migration. Collectively, our study highlights an unexpected adaptive transcriptional crosstalk between LRP1 and specific S1P receptors which accounts for S1P signalling in brain EC. Targeting of the LRP1/S1P signalling axis at the BBB may thus be considered in future therapeutic strategies. Citation Format: Amélie Vézina, Cyndia Charfi, Alain Zgheib, Borhane Annabi. Adaptive mechanisms upon LRP1 repression: Impact on sphingosine-1-phosphate-mediated signalling and migration of brain endothelial cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3364.
Published Version
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