Sphingomyelin synthase as a potential target for D609-induced apoptosis in U937 human monocytic leukemia cells

Aimin Meng, Chiara Luberto, Patrick Meier, Aiping Bai, Xiaofeng Yang, Yusuf A. Hannun, Daohong Zhou

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

Tricyclodecan-9-yl-xanthogenate (D609) is a selective tumor cytotoxic agent. However, the mechanisms of action of D609 against tumor cells have not been well established. Using U937 human monocytic leukemia cells, we examined the ability of D609 to inhibit sphingomyelin synthase (SMS), since inhibition of SMS may contribute to D609-induced tumor cell cytotoxicity via modulating the cellular levels of ceramide and diacylglycerol (DAG). The results showed that D609 is capable of inducing U937 cell death by apoptosis in a dose- and time-dependent manner. The induction of U937 cell apoptosis was associated with an inhibition of SMS activity and a significant increase in the intracellular level of ceramide and decrease in that of sphingomyelin (SM) and DAG, which resulted in an elevation of the ratio between ceramide and DAG favoring the induction of apoptosis. In addition, incubation of U937 cells with C 6-ceramide and/or H7 (a selective PKC inhibitor) reduced U937 cell viability; whereas pretreatment of the cells with a PKC activator, PMA or 1-oleoyl-2-acetylglycerol (OAG), attenuated D609-induced U937 cell apoptosis. These results suggest that SMS is a potential target of D609 and inhibition of SMS may contribute to D609-induced tumor cell death via modulation of the cellular levels of ceramide and DAG.

Original languageEnglish (US)
Pages (from-to)385-392
Number of pages8
JournalExperimental Cell Research
Volume292
Issue number2
DOIs
StatePublished - Jan 15 2004
Externally publishedYes

Keywords

  • Apoptosis
  • Ceramide
  • D609
  • Diacylglycerol
  • Sphingomyelin synthase

ASJC Scopus subject areas

  • Cell Biology

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