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FTY720 Induces Necroptosis by Regulating Ceramide Signaling at the Plasma Membrane
Author(s) -
Ndeto Rose,
Ogretmen Besim
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.655.1
Subject(s) - necroptosis , ceramide , microbiology and biotechnology , sphingolipid , sphingosine , fingolimod , sphingosine kinase , lipid signaling , sphingosine 1 phosphate , signal transduction , programmed cell death , kinase , protein phosphatase 2 , biology , ripk1 , chemistry , phosphorylation , biochemistry , receptor , phosphatase , immunology , apoptosis , multiple sclerosis
Sphingolipids, important signaling molecules in cells, have recently been explored as cancer therapy targets. FTY720 (Fingolimod, Gilenya) is an FDA approved sphingosine analogue drug used for the treatment of multiple sclerosis (MS). FTY720 is phosphorylated by sphingosine kinase 2 (SK2), to generate P‐FTY720 to exert its immunosuppressive properties through binding to sphingosine 1‐phosphate receptors (S1PRs). FTY720 also exhibits anti‐cancer properties. Our previous studies indicated that one of the mechanism by which FTY720 induces cell death is through necroptosis. FTY720, similar to ceramide, directly binds to I2PP2A/SET (Inhibitor 2 of PP2A), consequently activating the tumor suppressor protein phosphatase 2A (PP2A). The activated PP2A then induces cell death by stimulating the activity of Receptor‐Interacting Protein Kinase‐1 (RIPK1), involved in necroptosis signaling. It is known that FTY720 can modulate sphingolipids metabolism in cells. However, little is known about the roles of FTY720 in ceramide signaling and regulation of necroptosis in lung cancer. We hereby seek to investigate the mechanisms of FTY720 in inducing necroptosis with regard to ceramide signaling. Preliminary cell viability data indicate that inhibitors of ceramide generation partially protect cells against FTY720‐induced cell death. Interestingly, using confocal microscopy, we show that FTY720 and its non‐phosphorylatable analogues lead to the formation of specific ceramide‐multi‐protein complexes at the plasma membrane involved in plasma membrane disruption for induction of necroptosis. Future mechanistic studies will help us understand the details of how these ceramide‐dependent lipid‐protein complexes are formed at the plasma membrane and how they are involved in the regulation of necroptosis in response to cellular stress evoked by FTY720 and other therapeutic agents, leading to tumor suppression. Support or Funding Information RO1CA088932, RO1CA173687, P30GM103339