Fumonisin B1 induces apoptosis in cultured human keratinocytes through sphinganine accumulation and ceramide depletion.
Fumonisin B1 stimulates apoptosis in a variety of cell types and tissues. We examined the role of sphingolipid changes in fumonisin B1-stimulated apoptosis. Sphinganine accumulated rapidly, sphingosine levels remained unchanged, and ceramides decreased during fumonisin B1 exposure. Increased DNA fragmentation, decreased viability, and apoptotic morphology were observed in cells exposed to fumonisin B1, sphinganine, or N-acetylsphingosine. Co-exposure to N-acetylsphingosine or beta-chloroalanine, which blocks sphinganine accumulation, partially protected cells from fumonisin B1-induced apoptosis. These results illustrate three sphingolipid-dependent mechanisms for inducing apoptosis: accumulation of excess ceramide, accumulation of excess sphinganine, and depletion of ceramide or complex sphingolipids derived from ceramide.
Tolleson
W H
WH
Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA.
Couch
L H
LH
Melchior
W B
WB
Jenkins
G R
GR
Muskhelishvili
M
M
Muskhelishvili
L
L
McGarrity
L J
LJ
Domon
O
O
Morris
S M
SM
Howard
P C
PC
D017209:Apoptosis; D002264:Carboxylic Acids / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003114:Colony-Forming Units Assay; D053938:DNA Fragmentation / Q000187:drug effects; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D037341:Fumonisins; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013107:Sphingolipids / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013723:Teratogens / Q000494:pharmacology*; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
D002264:Carboxylic Acids; D002518:Ceramides; D004791:Enzyme Inhibitors; D037341:Fumonisins; C064769:N-acetylsphingosine; D013107:Sphingolipids; D013723:Teratogens; D015091:beta-Alanine; C006977:3-chloroalanine; C056933:fumonisin B1; D013110:Sphingosine; C005682:safingol