Document Detail

Endothelin-1 inhibits apoptosis through a sphingosine kinase 1-dependent mechanism in uterine leiomyoma ELT3 cells.
MedLine Citation:
PMID:  16959847     Owner:  NLM     Status:  MEDLINE    
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 ETB 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.
Marie-Noëlle Raymond; Christine Bole-Feysot; Yoshiko Banno; Zahra Tanfin; Philippe Robin
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-07
Journal Detail:
Title:  Endocrinology     Volume:  147     ISSN:  0013-7227     ISO Abbreviation:  Endocrinology     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-11-19     Completed Date:  2007-01-11     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5873-82     Citation Subset:  AIM; IM    
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.
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MeSH Terms
Apoptosis / drug effects*
Culture Media, Serum-Free / pharmacology
Cytoprotection / drug effects
Endothelin-1 / pharmacology*
Leiomyoma / enzymology*,  pathology
Myometrium / cytology,  drug effects
Phosphotransferases (Alcohol Group Acceptor) / physiology*
Tumor Cells, Cultured
Uterine Neoplasms / enzymology*,  pathology
Reg. No./Substance:
0/Culture Media, Serum-Free; 0/Endothelin-1; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/sphingosine kinase

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