Targeting glucosylceramide synthase synergizes with C6-ceramide nanoliposomes to induce apoptosis in natural killer cell leukemia

Rebecca J. Watters, Todd E. Fox, Su Fern Tan, Sriram Shanmugavelandy, Jacob E. Choby, Kathleen Broeg, Jiangang (Jason) Liao, Mark Kester, Myles C. Cabot, Thomas P. Loughran, Xin Liu

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Abstract

Natural killer (NK) cell leukemia is characterized by clonal expansion of CD3 - NK cells and comprises both chronic and aggressive forms. Currently no effective treatment exists, thus providing a need for identification of novel therapeutics. Lipidomic studies revealed a dysregulated sphingolipid metabolism as evidenced by decreased levels of overall ceramide species and increased levels of cerebrosides in leukemic NK cells, concomitant with increased glucosylceramide synthase (GCS) expression. GCS, a key enzyme of this pathway, neutralizes pro-apoptotic ceramide by transfer of a uridine diphosphate (UDP)-glucose. Thus, we treated both rat and human leukemic NK cells in combination with: (1) exogenous C6-ceramide nanoliposomes in order to target mitochondria and increase physiological pro-apoptotic levels of long chain ceramide, and (2) 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP), an inhibitor of GCS. Co-administration of C6-ceramide nanoliposomes and PPMP elicited an increase in endogenous long-chain ceramide species, which led to cellular apoptosis in a synergistic manner via the mitochondrial intrinsic cell death pathway in leukemic NK cells.

Original languageEnglish (US)
Pages (from-to)1288-1296
Number of pages9
JournalLeukemia and Lymphoma
Volume54
Issue number6
DOIs
StatePublished - Jun 1 2013

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All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Watters, R. J., Fox, T. E., Tan, S. F., Shanmugavelandy, S., Choby, J. E., Broeg, K., Liao, J. J., Kester, M., Cabot, M. C., Loughran, T. P., & Liu, X. (2013). Targeting glucosylceramide synthase synergizes with C6-ceramide nanoliposomes to induce apoptosis in natural killer cell leukemia. Leukemia and Lymphoma, 54(6), 1288-1296. https://doi.org/10.3109/10428194.2012.752485