Sphingosine-dependent apoptosis: a unified concept based on multiple mechanisms operating in concert.
Exposure of 3T3/A31 cells to serum-free medium, one type of apoptotic stimulus, causes a rapid increase in the sphingosine (Sph) level, which initiates a series of processes: (i) activation of caspase 3 through an enhanced "cascade" of caspases, (ii) release of the C-terminal-half kinase domain of PKCdelta (PKCdelta KD) by caspase 3, and (iii) activation of Sph-dependent kinase 1 (SDK1), which was previously identified as PKCdelta KD. The activation of caspase 3 and release of PKCdelta KD are inhibited strongly by the incubation of cells with the ceramidase inhibitor D-erythro-2-tetradecanoylamino-1-phenyl-1-propanol and, to a much lesser extent, by L-cycloserine, an inhibitor of de novo ceramide synthesis. Exogenous addition of Sph or N,N-dimethyl-Sph to U937 cells causes caspase 3 activation and release of PKCdelta KD (SDK1), leading to apoptosis. The Sph-induced apoptotic process associated with activation of caspase 3 and release of PKCdelta KD (SDK1) may promote the proapoptotic effect of BAD or BAX through an increase of phosphorylated 14-3-3. In addition, Sph induces apoptosis through a separate process: the blocking of "survival signal" through the Akt kinase pathway induced by alpha3beta1-mediated cell adhesion to laminin 10/11 in extracellular matrix. We hereby propose a unified concept of Sph-dependent apoptosis based on these multiple mechanisms operating in concert.
Suzuki
Erika
E
Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122-4302, USA.
Handa
Kazuko
K
Toledo
Marcos S
MS
Hakomori
Senitiroh
S
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000502:physiology; D020298:U937 Cells
C064769:N-acetylsphingosine; D013110:Sphingosine