Abstract 4298: FTY720 induces necroptosis in lung cancer by modulating ceramide signaling at the plasma membrane

Abstract

Abstract Sphingolipids are important signaling molecules in cells and 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 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. Previous studies have shown 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 data indicate that inhibitors of ceramide generation partially protect cells against FTY720-induced cell death. Interestingly, FTY720 and non-phosphorylated FTY720 analogues do not affect ceramide generation, but lead to the formation of cancer specific ceramide-multi-protein complexes at the plasma membrane. Our studies show a role of these complexes in inducing plasma membrane rupture, a key phenomenon in necroptosis. Further elucidation of these novel structures will be helpful in improving cancer therapeutics that further promote the formation these structures hence more cell death. Citation Format: Rose Nganga. FTY720 induces necroptosis in lung cancer by modulating ceramide signaling at the plasma membrane [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4298. doi:10.1158/1538-7445.AM2017-4298