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

Megan M. Young, Van Bui, Chong Chen, Hong Gang Wang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Article number847
JournalCell Death and Disease
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2019

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Fingerprint

Dive into the research topics of 'FTY720 induces non-canonical phosphatidylserine externalization and cell death in acute myeloid leukemia'. Together they form a unique fingerprint.

Cite this