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Originally published In Press as doi:10.1194/jlr.M700171-JLR200 on November 16, 2007

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Journal of Lipid Research, Vol. 49, 295-307, February 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Role of lysophosphatidic acid in the regulation of uterine leiomyoma cell proliferation by phospholipase D and autotaxin

Emmanuelle Billon-Denis, Zahra Tanfin1 and Philippe Robin

University Paris Sud, Institut de Biochimie et Biophysique Moléculaire et Cellulaire Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8619, Équipe Signalisation et Régulations Cellulaires, Orsay, France

Published, JLR Papers in Press, November 16, 2007.

1 To whom correspondence should be addressed. e-mail: zahra.tanfin{at}u-psud.fr

Phospholipase D (PLD) hydrolyzes phosphatidylcholine into phosphatidic acid (PA), a lipidic mediator that may act directly on cellular proteins or may be metabolized into lysophosphatidic acid (LPA). We previously showed that PLD contributed to the mitogenic effect of endothelin-1 (ET-1) in a leiomyoma cell line (ELT3 cells). In this work, we tested the ability of exogenous PA and PLD from Streptomyces chromofuscus (scPLD) to reproduce the effect of endogenous PLD in ELT3 cells and the possibility that these agents acted through LPA formation. We found that PA, scPLD, and LPA stimulated thymidine incorporation. LPA and scPLD induced extracellular signal-regulated kinase (ERK1/2) mitogen-activated protein kinase activation. Using Ki16425, an LPA1/LPA3 receptor antagonist and small interfering RNA targeting LPA1 receptor, we demonstrated that scPLD acted through LPA production and LPA1 receptor activation. We found that scPLD induced LPA production by hydrolyzing lysophosphatidylcholine through its lysophospholipase D (lysoPLD) activity. Autotaxin (ATX), a naturally occurring lysoPLD, reproduced the effects of scPLD. By contrast, endogenous PLD stimulated by ET-1 failed to produce LPA. These results demonstrate that scPLD stimulated ELT3 cell proliferation by an LPA-dependent mechanism, different from that triggered by endogenous PLD. These data suggest that in vivo, an extracellular lysoPLD such as ATX may participate in leiomyoma growth through local LPA formation.

Supplementary key words extracellular signal-regulated kinase • lysophosphatidylcholine • phosphatidic acid • endothelin-1 • uterine tumor


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