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.
Highlights
Sphingolipids are a class of complex cellular lipids that serve both a structural role in the cellular membrane as well as an intracellular signaling role within the cell
It was further demonstrated that this dose-dependent cell death induced by nanoliposomal C6-ceramide was observed in primary chronic lymphocytic leukemia (CLL) patient cells but not in Peripheral blood mononuclear cells (PBMCs) isolated from normal donors (Figure 1E)
The present study identifies dysregulated glucose metabolism as a novel target in CLL
Summary
Sphingolipids are a class of complex cellular lipids that serve both a structural role in the cellular membrane as well as an intracellular signaling role within the cell. Several types of sphingolipid metabolites have been shown to influence the balance between mitogenesis and apoptosis. Ceramide inhibits cell proliferation and induces apoptosis via mechanisms such as dephosphorylation and/or inactivation of molecules including Akt, phospholipase D, ERK, Bcl-2, survivin, PKC-α, and pRB [4,5,6], as well as activation of JNK kinases[4,7], or PKC zeta which, results in suppression of Akt-dependent mitogenesis [8]. Many cancer chemotherapies have been shown to generate endogenous ceramide, and when de novo generation of ceramide is inhibited, the cellular response to cytotoxic chemotherapeutic agents decreases [4]. It has previously been shown that accumulation of endogenous ceramides or exogenous ceramide treatment is more toxic to tumor cells than to normal cells [6,9].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
