Differential signaling of sphingosine derivatives in U937 human monocytes depends on the degree of N-methylation.
Previously, we studied N,N-dimethyl-D-erythro-sphingosine (DMS)-induced cell death and signaling in U937 human monocytes; we found that DMS-induced sphingosine kinase- and PKC-independent apoptosis. In the present study, we studied apoptotic responses by three N-methyl derivatives of sphingosine: N-monomethyl-D-erythro-sphingosine (MMS), N,N,N-trimethyl-D-erythro-sphingosine (TMS), and D-erythro-sphingosine (SPH). The potency order in the apoptotic response was DMS>or=MMS>TMS>SPH. We compared cellular responses to the derivatives in terms of activities of MAPK signaling molecules, mitochondrial membrane potential (DeltaPsi(m)), and reactive oxygen species (ROS) generation. Our results suggest that the degree of N-methylation affects the apoptosis-inducing capacity and other related responses including MAPK modulation, DeltaPsi(m), and ROS generation. Dimethylation and monomethylation on the C2 amine of sphingosine enhance the apoptotic response; however, trimethylation induces differential modulation of signaling molecules and less cytotoxicity. Our investigation will be useful for understanding the actions of sphingolipids in apoptosis and for developing chemotherapeutics based on DMS structure.
Kim
Hyo-Lim
HL
Laboratory of Pharmacology, College of Pharmacy (BK21 Project) and Longevity Life Science and Technology Institutes, Pusan National University, Busan 609-735, Republic of Korea.
Han
Mijin
M
Im
Dong-Soon
DS
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008745:Methylation; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020298:U937 Cells
D017382:Reactive Oxygen Species; C061800:N,N-dimethylsphingosine; D013110:Sphingosine