Yes / 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 receptordependent
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 þ 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. / Diabetes UK; British Heart Foundation
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/7924 |
| Date | 16 October 2013 |
| Creators | Rutherford, C., Childs, S., Ohotski, J., McGlynn, L., Riddick, M., MacFarlane, S., Tasker, D., Pyne, S., Pyne, N.J., Edwards, J., Palmer, Timothy M. |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Article, Published version |
| Rights | © 2013 Macmillan Publishers Limited. Full-text reproduced in accordance with the publisher's self-archiving policy. This work is licensed under a Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0/, CC-BY |
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