Regulation of cell survival by sphingosine-1-phosphate receptor S1P 1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1

Rutherford, C; Childs, S; Ohotski, J; McGlynn, L; Riddick, M; MacFarlane, S; Tasker, D; Pyne, S; Pyne, N J; Edwards, J; Palmer, T M

Abstract

Although the ability of bioactive lipid sphingosine-1-phosphate (S1P) to positively regulate anti-apoptotic/pro-survival responses by binding to S1P1 is well known, the molecular mechanisms remain unclear. Here we demonstrate that expression of S1P1 renders CCL39 lung fibroblasts resistant to apoptosis following growth factor withdrawal. Resistance to apoptosis was associated with attenuated accumulation of pro-apoptotic BH3-only protein Bim. However, although blockade of extracellular signal-regulated kinase (ERK) activation could reverse S1P1-mediated suppression of Bim accumulation, inhibition of caspase-3 cleavage was unaffected. Instead S1P1-mediated inhibition of caspase-3 cleavage was reversed by inhibition of phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC), which had no effect on S1P1 regulation of Bim. However, S1P1 suppression of caspase-3 was associated with increased expression of anti-apoptotic protein Mcl-1, the expression of which was also reduced by inhibition of PI3K and PKC. A role for the induction of Mcl-1 in regulating endogenous S1P receptor-dependent pro-survival responses in human umbilical vein endothelial cells was confirmed using S1P receptor agonist FTY720-phosphate (FTY720P). FTY720P induced a transient accumulation of Mcl-1 that was associated with a delayed onset of caspase-3 cleavage following growth factor withdrawal, whereas Mcl-1 knockdown was sufficient to enhance caspase-3 cleavage even in the presence of FTY720P. Consistent with a pro-survival role of S1P1 in disease, analysis of tissue microarrays from ER(+) breast cancer patients revealed a significant correlation between S1P1 expression and tumour cell survival. In these tumours, S1P1 expression and cancer cell survival were correlated with increased activation of ERK, but not the PI3K/PKB pathway. In summary, pro-survival/anti-apoptotic signalling from S1P1 is intimately linked to its ability to promote the accumulation of pro-survival protein Mcl-1 and downregulation of pro-apoptotic BH3-only protein Bim via distinct signalling pathways. However, the functional importance of each pathway is dependent on the specific cellular context.

Citation

Rutherford, C., Childs, S., Ohotski, J., McGlynn, L., Riddick, M., MacFarlane, S., Tasker, D., Pyne, S., Pyne, N. J., Edwards, J., & Palmer, T. M. (2013). Regulation of cell survival by sphingosine-1-phosphate receptor S1P 1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1. Cell Death and Disease, 4(11), Article e927. https://doi.org/10.1038/cddis.2013.455

• Journal Article Type: Article
• Acceptance Date: Oct 16, 2013
• Online Publication Date: Nov 21, 2013
• Publication Date: Nov 1, 2013
• Deposit Date: Oct 30, 2018
• Publicly Available Date: Nov 7, 2018
• Journal: Cell Death & Disease
• Print ISSN: 2041-4889
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 4
• Issue: 11
• Article Number: e927
• DOI: https://doi.org/10.1038/cddis.2013.455
• Keywords: Apoptosis; Breast cancer; Cell signaling
• Public URL: https://hull-repository.worktribe.com/output/1137573
• Publisher URL: https://www.nature.com/articles/cddis2013455
• Contract Date: Oct 30, 2018