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FTY720 induces non-canonical phosphatidylserine externalization and cell death in acute myeloid leukemia.


ABSTRACT: FTY720 (fingolimod) is a FDA-approved sphingosine analog that is phosphorylated in vivo to modulate sphingosine-1-phosphate receptor (S1PR) signaling for immunosuppression in patients with refractory multiple sclerosis. FTY720 also exhibits promising anticancer efficacy in several preclinical models. While FTY720-induced cytotoxicity is not due to S1PR signaling, the mechanism remains unclear and is reported to occur through various cell death pathways. Here, we performed a systematic, mechanistic study of FTY720-induced cell death in acute myeloid leukemia (AML). We found that FTY720 induced cell death in a panel of genetically diverse AML cell lines that was accompanied by rapid phosphatidylserine (PS) externalization. Importantly, FTY720-induced PS exposure was not due to any direct effects on plasma membrane integrity and was independent of canonical signaling by regulated cell death pathways known to activate lipid flip-flop, including caspase-dependent apoptosis/pyroptosis, necroptosis, ferroptosis, and reactive oxygen species-mediated cell death. Notably, PS exposure required cellular vacuolization induced by defects in endocytic trafficking and was suppressed by the inhibition of PP2A and shedding of Annexin V-positive subcellular particles. Collectively, our studies reveal a non-canonical pathway underlying PS externalization and cell death in AML to provide mechanistic insight into the antitumor properties of FTY720.

SUBMITTER: Young MM 

PROVIDER: S-EPMC6838108 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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FTY720 induces non-canonical phosphatidylserine externalization and cell death in acute myeloid leukemia.

Young Megan M MM   Bui Van V   Chen Chong C   Wang Hong-Gang HG  

Cell death & disease 20191107 11


FTY720 (fingolimod) is a FDA-approved sphingosine analog that is phosphorylated in vivo to modulate sphingosine-1-phosphate receptor (S1PR) signaling for immunosuppression in patients with refractory multiple sclerosis. FTY720 also exhibits promising anticancer efficacy in several preclinical models. While FTY720-induced cytotoxicity is not due to S1PR signaling, the mechanism remains unclear and is reported to occur through various cell death pathways. Here, we performed a systematic, mechanist  ...[more]

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