Phosphorylation of the immunomodulator FTY720 inhibits programmed cell death of fibroblasts via the S1P3 receptor subtype and Bcl-2 activation.
BACKGROUND
FTY720, a synthetic compound produced by modification of a metabolite from Isaria sinclairii, is known as a unique immunosuppressive agent that exerts its activity by inhibiting lymphocyte egress from secondary lymphoid tissues. FTY720 is phosphorylated in vivo by sphingosine kinase 2 to FTY720-phosphate (FTY720-P), which acts as a potent sphingosine-1-phosphate (S1P) receptor agonist. Despite its homology to S1P, which exerts antiapoptotic actions in different cells, FTY720 has also been reported to be able to induce apoptosis in a variety of cells.


METHODS
Therefore, we investigated the action of both, FTY720 and its phosphorylated version FTY720-P, on apoptosis. Moreover, signalling pathways of apoptosis in response to FTY720 and FTY720-P were examined.


CONCLUSIONS
Although FTY720 acts apoptotic at micromolar concentrations in human fibroblasts the phosphorylated compound FTY720-P possesses a pronounced antiapoptotic effect counteracting FTY720-induced programmed cell death. Interestingly, none of the classical antiapoptotic pathways like MAP kinases, Akt or mTOR play a role in the protective role of FTY720-P. Most important, we identified that the S1P(3) receptor subtype is involved in the antiapoptotic action of FTY720-P leading to an increased phosphorylation of Bcl-2 and changes in the mitochondrial membrane potential.
Potteck
Henrik
H
Faculty of Mathematics and Natural Science, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
Nieuwenhuis
Barbara
B
Lüth
Anja
A
van der Giet
Markus
M
Kleuser
Burkhard
B
D017209:Apoptosis / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010755:Organophosphates / Q000494:pharmacology*; D010766:Phosphorylation; D011409:Propylene Glycols / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
C525008:FTY 720P; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D010755:Organophosphates; D011409:Propylene Glycols; D019253:Proto-Oncogene Proteins c-bcl-2; D049349:Receptors, Lysosphingolipid; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine