title: Thymineless death in F10-treated AML cells occurs via lipid raft depletion and Fas/FasL co-localization in the plasma membrane with activation of the extrinsic apoptotic pathway.
abstract: The polymeric fluoropyrimidine F10 displays excellent anti-leukemia activity in pre-clinical models of acute myelogenous leukemia (AML) through dual targeting of thymidylate synthase and DNA topoisomerase 1. Here we report that F10 activates the extrinsic apoptotic pathway in AML cells by enhancing localization of Fas and Fas ligand (FasL) at the plasma membrane and while reducing overall lipid raft levels promotes Fas/FasL co-localization in remaining lipid rafts. The HMG-CoA synthase inhibitor simvastatin was synergistic with F10 and induced cell death via similar apoptotic processes. Our results are consistent with diverse processes activating a common apoptotic pathway characterized by reduced overall levels of lipid rafts and Fas/FasL co-localization in the plasma membrane, including in remaining lipid rafts which may play a role in both cell-survival and cell death signaling.
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States; Comprehensive Cancer Center at Wake Forest University, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States; Molecular Medicine and Translational Science, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States. Electronic address: bgmeiner@wakehealth.edu.
authors.forename: William H
authors.initials: WH
authors.lastname: Gmeiner
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
authors.forename: Jamie
authors.initials: J
authors.lastname: Jennings-Gee
authors.affiliation: Molecular Medicine and Translational Science, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Stuart
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States; Comprehensive Cancer Center at Wake Forest University, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States; Department of Hematology/Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Pardee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053222:Fas Ligand Protein / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021962:Membrane Microdomains / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D009363:Neoplasm Proteins; D011743:Pyrimidines; D019014:fas Receptor
keywords: Apoptosis; DNA; F10; Fas; Lipid rafts