TY - JOUR
T1 - FTY720 induces non-canonical phosphatidylserine externalization and cell death in acute myeloid leukemia
AU - Young, Megan M.
AU - Bui, Van
AU - Chen, Chong
AU - Wang, Hong Gang
N1 - Funding Information:
This work was funded in part by National Institutes of Health Grants CA171983 and CA222349, and the Lois High Berstler Fund and Four Diamonds Fund of Penn State College of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the staff of the Penn State College of Medicine Flow Cytometry Core Facility for assistance with flow cytometry analysis.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41419-019-2080-5
DO - 10.1038/s41419-019-2080-5
M3 - Article
C2 - 31699964
AN - SCOPUS:85074709467
VL - 10
JO - Cell Death and Disease
JF - Cell Death and Disease
SN - 2041-4889
IS - 11
M1 - 847
ER -