title: C6-ceramide nanoliposomes target the Warburg effect in chronic lymphocytic leukemia.
abstract: Ceramide is a sphingolipid metabolite that induces cancer cell death. When C6-ceramide is encapsulated in a nanoliposome bilayer formulation, cell death is selectively induced in tumor models. However, the mechanism underlying this selectivity is unknown. As most tumors exhibit a preferential switch to glycolysis, as described in the "Warburg effect", we hypothesize that ceramide nanoliposomes selectively target this glycolytic pathway in cancer. We utilize chronic lymphocytic leukemia (CLL) as a cancer model, which has an increased dependency on glycolysis. In CLL cells, we demonstrate that C6-ceramide nanoliposomes, but not control nanoliposomes, induce caspase 3/7-independent necrotic cell death. Nanoliposomal ceramide inhibits both the RNA and protein expression of GAPDH, an enzyme in the glycolytic pathway, which is overexpressed in CLL. To confirm that ceramide targets GAPDH, we demonstrate that downregulation of GAPDH potentiates the decrease in ATP after ceramide treatment and exogenous pyruvate treatment as well as GAPDH overexpression partially rescues ceramide-induced necrosis. Finally, an in vivo murine model of CLL shows that nanoliposomal C6-ceramide treatment elicits tumor regression, concomitant with GAPDH downregulation. We conclude that selective inhibition of the glycolytic pathway in CLL cells with nanoliposomal C6-ceramide could potentially be an effective therapy for leukemia by targeting the Warburg effect.
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, United States of America ; Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Lindsay K
authors.initials: LK
authors.lastname: Ryland
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Ushma A
authors.initials: UA
authors.lastname: Doshi
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Sriram S
authors.initials: SS
authors.lastname: Shanmugavelandy
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Fox
authors.affiliation: Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Cesar
authors.initials: C
authors.lastname: Aliaga
authors.affiliation: Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Broeg
authors.affiliation: Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Kendall Thomas
authors.initials: KT
authors.lastname: Baab
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, United States of America ; Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Young
authors.affiliation: Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Osman
authors.initials: O
authors.lastname: Khan
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Haakenson
authors.affiliation: Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Nancy Ruth
authors.initials: NR
authors.lastname: Jarbadan
authors.affiliation: Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Liao
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, United States of America ; Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.affiliation: Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Feith
authors.affiliation: Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America ; Department of Medicine, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.affiliation: Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America ; Department of Medicine, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, United States of America ; Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology*; D002518:Ceramides / Q000378:metabolism* / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000503:physiopathology*; D008081:Liposomes / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008858:Microscopy, Phase-Contrast; D053758:Nanoparticles / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002518:Ceramides; D017931:DNA Primers; D008081:Liposomes; C492068:N-hexanoyldihydrosphingosine; D000255:Adenosine Triphosphate; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases