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J. Biol. Chem., Vol. 281, Issue 13, 8518-8527, March 31, 2006

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Regulation of Autophagy by Sphingosine Kinase 1 and Its Role in Cell Survival during Nutrient Starvation^*

Grégory Lavieu, Francesca Scarlatti, Giusy Sala, Stéphane Carpentier^¶, Thierry Levade^¶, Riccardo Ghidoni, Joëlle Botti^||, and Patrice Codogno^||1

From the INSERM U504, Institut André Lwoff, 94807 Villejuif Cedex, France, ^||INSERM U756, Faculté de Pharmacie, Université Paris-Sud, 92296 Châtenay-Malabry, France, the Laboratory of Biochemistry and Molecular Biology, San Paolo Medical School, via A. di Rudiní 8, 20142 Milan, Italy, and the ^¶INSERM U466, Institut Louis Bugnard, Centre Hospitalier Universitaire de Rangueil, BP 84225, 31432 Toulouse Cedex 4, France

The sphingolipid ceramide induces macroautophagy (here called autophagy) and cell death with autophagic features in cancer cells. Here we show that overexpression of sphingosine kinase 1 (SK1), an enzyme responsible for the production of sphingosine 1-phosphate (S1P), in MCF-7 cells stimulates autophagy by increasing the formation of LC3-positive autophagosomes and the rate of proteolysis sensitive to the autophagy inhibitor 3-methyladenine. Autophagy was blocked in the presence of dimethylsphingosine, an inhibitor of SK activity, and in cells expressing a catalytically inactive form of SK1. In SK1^wt-overexpressing cells, however, autophagy was not sensitive to fumonisin B1, an inhibitor of ceramide synthase. In contrast to ceramide-induced autophagy, SK1(S1P)-induced autophagy is characterized by (i) the inhibition of mammalian target of rapamycin signaling independently of the Akt/protein kinase B signaling arm and (ii) the lack of robust accumulation of the autophagy protein Beclin 1. In addition, nutrient starvation induced both the stimulation of autophagy and SK activity. Knocking down the expression of the autophagy protein Atg7 or that of SK1 by siRNA abolished starvation-induced autophagy and increased cell death with apoptotic hallmarks. In conclusion, these results show that SK1(S1P)-induced autophagy protects cells from death with apoptotic features during nutrient starvation.

Received for publication, June 7, 2005 , and in revised form, January 12, 2006.

^* This work was supported by institutional funding from the Institut National de la Santé et de la Recherche Médicale (INSERM) and from University Paris-Sud, by grants from the Association pour la Recherche sur le Cancer (n°3503 to PC) and a bilateral French-Italian exchange program (Galileo). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: INSERM U756 Faculté de Pharmacie 92296 Châtenay-Malabry, France. Tel.: 33-1-468-35528; Fax: 33-1-468-35844; E-mail: codogno{at}vjf.inserm.fr.

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