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Sphingomyelin synthase as a potential target for D609-induced apoptosis in U937 human monocytic leukemia cells
Aimin Meng1, Chiara Luberto, Patrick Meier
1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
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.
Insights
Tricyclodecan-9-yl-xanthogenate (D609) induces cancer cell death by apoptosis. D609 inhibits sphingomyelin synthase (SMS), altering ceramide and diacylglycerol levels, which contributes to its tumor cytotoxic effects.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Tricyclodecan-9-yl-xanthogenate (D609) is a selective tumor cytotoxic agent.
- The precise mechanisms underlying D609's action against tumor cells remain incompletely understood.
Purpose of the Study:
- To investigate the inhibitory effect of D609 on sphingomyelin synthase (SMS) in U937 human monocytic leukemia cells.
- To elucidate whether SMS inhibition contributes to D609-induced cytotoxicity by modulating cellular ceramide and diacylglycerol (DAG) levels.
Main Methods:
- U937 cells were treated with D609 to assess apoptosis induction, SMS activity, and intracellular lipid levels (ceramide, sphingomyelin, DAG).
- The role of protein kinase C (PKC) was evaluated using PKC inhibitors (H7) and activators (PMA, OAG).
Main Results:
- D609 induced U937 cell apoptosis in a dose- and time-dependent manner.
- D609 treatment inhibited SMS activity, increased intracellular ceramide, and decreased sphingomyelin (SM) and DAG levels.
- The ceramide/DAG ratio elevation correlated with apoptosis induction; PKC modulation affected D609-induced apoptosis.
Conclusions:
- Sphingomyelin synthase (SMS) is identified as a potential molecular target of D609.
- Inhibition of SMS by D609 contributes to tumor cell death through the modulation of ceramide and DAG signaling pathways.
