C6-ceramide nanoliposomes target the warburg effect in chronic lymphocytic leukemia

Lindsay K. Ryland, Ushma A. Doshi, Sriram S. Shanmugavelandy, Todd E. Fox, Cesar Aliaga, Kathleen Broeg, Kendall Thomas Baab, Megan Marie Young, Osman Khan, Jeremy K. Haakenson, Nancy Ruth Jarbadan, Jiangang (Jason) Liao, Hong-Gang Wang, David J. Feith, Thomas P. Loughran, Xin Liu, Mark Kester

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere84648
JournalPloS one
Volume8
Issue number12
DOIs
StatePublished - Dec 19 2013

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lymphocytic leukemia
ceramides
Ceramides
B-Cell Chronic Lymphocytic Leukemia
long term effects
glycolysis
Cell death
Tumors
Neoplasms
Cell Death
Glycolysis
Down-Regulation
cell death
neoplasms
Caspase 7
Sphingolipids
Metabolites
Pyruvic Acid
Caspase 3
N-caproylsphingosine

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Ryland, L. K., Doshi, U. A., Shanmugavelandy, S. S., Fox, T. E., Aliaga, C., Broeg, K., ... Kester, M. (2013). C6-ceramide nanoliposomes target the warburg effect in chronic lymphocytic leukemia. PloS one, 8(12), [e84648]. https://doi.org/10.1371/journal.pone.0084648
Ryland, Lindsay K. ; Doshi, Ushma A. ; Shanmugavelandy, Sriram S. ; Fox, Todd E. ; Aliaga, Cesar ; Broeg, Kathleen ; Baab, Kendall Thomas ; Young, Megan Marie ; Khan, Osman ; Haakenson, Jeremy K. ; Jarbadan, Nancy Ruth ; Liao, Jiangang (Jason) ; Wang, Hong-Gang ; Feith, David J. ; Loughran, Thomas P. ; Liu, Xin ; Kester, Mark. / C6-ceramide nanoliposomes target the warburg effect in chronic lymphocytic leukemia. In: PloS one. 2013 ; Vol. 8, No. 12.
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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.",
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Ryland, LK, Doshi, UA, Shanmugavelandy, SS, Fox, TE, Aliaga, C, Broeg, K, Baab, KT, Young, MM, Khan, O, Haakenson, JK, Jarbadan, NR, Liao, JJ, Wang, H-G, Feith, DJ, Loughran, TP, Liu, X & Kester, M 2013, 'C6-ceramide nanoliposomes target the warburg effect in chronic lymphocytic leukemia', PloS one, vol. 8, no. 12, e84648. https://doi.org/10.1371/journal.pone.0084648

C6-ceramide nanoliposomes target the warburg effect in chronic lymphocytic leukemia. / Ryland, Lindsay K.; Doshi, Ushma A.; Shanmugavelandy, Sriram S.; Fox, Todd E.; Aliaga, Cesar; Broeg, Kathleen; Baab, Kendall Thomas; Young, Megan Marie; Khan, Osman; Haakenson, Jeremy K.; Jarbadan, Nancy Ruth; Liao, Jiangang (Jason); Wang, Hong-Gang; Feith, David J.; Loughran, Thomas P.; Liu, Xin; Kester, Mark.

In: PloS one, Vol. 8, No. 12, e84648, 19.12.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - C6-ceramide nanoliposomes target the warburg effect in chronic lymphocytic leukemia

AU - Ryland, Lindsay K.

AU - Doshi, Ushma A.

AU - Shanmugavelandy, Sriram S.

AU - Fox, Todd E.

AU - Aliaga, Cesar

AU - Broeg, Kathleen

AU - Baab, Kendall Thomas

AU - Young, Megan Marie

AU - Khan, Osman

AU - Haakenson, Jeremy K.

AU - Jarbadan, Nancy Ruth

AU - Liao, Jiangang (Jason)

AU - Wang, Hong-Gang

AU - Feith, David J.

AU - Loughran, Thomas P.

AU - Liu, Xin

AU - Kester, Mark

PY - 2013/12/19

Y1 - 2013/12/19

N2 - 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.

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