Sphingosine-1-phosphate as a “come and get me” signal during apoptosis

ALVAREZ SE; GUDE DR; PAUGH SW; MITRA P; GRIFFITHS R; BARBOUR S; MILSTIEN S; SPIEGEL S

Richmond, VA USA

Congreso; American Cancer Society; 2007

Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates myriad important cellular processes including growth, survival, cytoskeleton rearrangements, motility, and immunity. The two sphingosine kinase isoforms, SphK1 and SphK2, that produce S1P, are inhibited by N,N-dimethylsphingosine (DMS). We found that treatment of Jurkat and U937 leukemia cells with DMS surprisingly causes a large increase in expression of SphK1 concomitant with induction of apoptosis. Another SphK inhibitor, D,L-threo-dihydro-sphingosine, also induced apoptosis and produced dramatic increases in SphK1 expression in these cells. Similar effects were observed with the apoptosis inducing chemotherapeutic drug doxorubicin, which also stimulated SphK1 expression and activity and promoted S1P secretion. Apoptotic cells secrete chemotactic factor(s) in a caspase-dependent manner to attract phagocytic cells. The pan caspase inhibitor ZVAD not only reduced doxorubicin-induced lethality but also increased expression of SphK1 and secretion of S1P. Moreover, we found that S1P potently stimulates chemotaxis of monocytic cells, primary monocytes, and macrophages. Collectively, our data suggests that apoptotic cells may upregulate 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 and subsequent immune system activation. This work was supported by NIH grant 37 GM043880 and NCI grant R01CA61774.