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Endothelin-1 Inhibits Apoptosis through a Sphingosine Kinase 1-Dependent Mechanism in Uterine Leiomyoma ELT3 Cells

Signalisation et Régulations Cellulaires (M.N.-R., C.B.-F., Z.T., P.R.), Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8619, Université Paris Sud, 91 405 Orsay Cedex, France; and Department of Cell Signaling (Y.B.), Gifu University, Graduate School of Medicine, Gifu 504-0838, Japan

Address all correspondence and requests for reprints to: Zahra Tanfin, Signalisation et Régulations Cellulaires, Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8619, Bâtiment 430, Université Paris Sud, 91 S/R/C 405 Orsay Cedex, France. E-mail: zahra.tanfin{at}erc.u-psud.fr.

Uterine leiomyomas, or fibroids, are the most common tumors of the myometrium. The ELT3 cell line, derived from Eker rat leiomyoma, has been successfully used as a model for the study of leiomyomas. We have demonstrated previously the potent mitogenic properties of the peptidic hormone endothelin (ET)-1 in this cell line. Here we investigated the antiapoptotic effect of ET-1 in ELT3 cells. We found that 1) serum starvation of ELT3 cells induced an apoptotic process characterized by cytochrome c release from mitochondria, caspase-3/7 activation, nuclei condensation and DNA fragmentation; 2) ET-1 prevented the apoptotic process; and 3) this effect of ET-1 was fully reproduced by ET_B agonists. In contrast, no antiapoptotic effect of ET-1 was observed in normal myometrial cells. A pharmacological approach showed that the effect of ET-1 on caspase-3/7 activation in ELT3 cells was not dependent on phosphatidylinositol 3-kinase, ERK1/2, or phospholipase D activities. However, inhibitors of sphingosine kinase-1 (SphK1), dimethylsphingosine and threo-dihydrosphingosine, reduced the effect of ET-1 by about 50%. Identical results were obtained when SphK1 expression was down-regulated in ELT3 cells transfected with SphK1 small interfering RNA. Furthermore, serum starvation induced a decrease in SphK1 activity that was prevented by ET-1 without affecting the level of SphK1 protein expression. Finally, sphingosine 1-phosphate, the product of SphK activity, was as efficient as ET-1 in inhibiting serum starvation-induced caspase-3/7 activation. Together, these results demonstrate that ET-1 possesses a potent antiapoptotic effect in ELT3 cells that involves sphingolipid metabolism through the activation of SphK1.

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