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This Article Full Text Full Text (PDF) All Versions of this Article: fj.08-107169v1 22/8/2629    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gude, D. R. Articles by Spiegel, S. PubMed PubMed Citation Articles by Gude, D. R. Articles by Spiegel, S.

Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal

David R. Gude^*,1, Sergio E. Alvarez^*,1, Steven W. Paugh^*, Poulami Mitra^*, JiaDe Yu^*, Rachael Griffiths^*, Suzanne E. Barbour^*, Sheldon Milstien and Sarah Spiegel^*,2

^* Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA; and

National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA

² Correspondence: Department of Biochemistry and Molecular Biology, VCU School of Medicine, 1101 E. Marshall St., 2011 Sanger Hall, Richmond, VA 23298, USA. E-mail: sspiegel{at}vcu.edu

Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates myriad important cellular processes, including growth, survival, cytoskeleton rearrangements, motility, and immunity. Here we report that treatment of Jurkat and U937 leukemia cells with the pan-sphingosine kinase (SphK) inhibitor N,N-dimethylsphingosine to block S1P formation surprisingly caused a large increase in expression of SphK1 concomitant with induction of apoptosis. Another SphK inhibitor, D,L-threo-dihydrosphingosine, also induced apoptosis and produced dramatic increases in SphK1 expression. However, up-regulation of SphK1 was not a specific effect of its inhibition but rather was a consequence of apoptotic stress. The chemotherapeutic drug doxorubicin, a potent inducer of apoptosis in these cells, also stimulated SphK1 expression and activity and promoted S1P secretion. The caspase inhibitor ZVAD reduced not only doxorubicin-induced lethality but also the increased expression of SphK1 and secretion of S1P. Apoptotic cells secrete chemotactic factors to attract phagocytic cells, and we found that S1P potently stimulated chemotaxis of monocytic THP-1 and U937 cells and primary monocytes and macrophages. Collectively, our data suggest that apoptotic cells may up-regulate SphK1 to produce and secrete S1P that serves as a "come-and-get-me" signal for scavenger cells to engulf them in order to prevent necrosis.—Gude, D. R., Alvarez, S. E., Paugh, S. W., Mitra, P., Yu, J., Griffiths, R., Barbour, S. E., Milstien, S., Spiegel, S. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal.

Key Words: chemotaxis • leukemia cells • monocytes • secretion