Contribution of phospholipase D in endothelin-1-mediated extracellular signal-regulated kinase activation and proliferation in rat uterine leiomyoma cells.
Endothelin (ET)-1 is a mitogenic factor in numerous cell types, including rat myometrial cells. In the present study, we investigated the potential role of ET-1 in the proliferation of tumoral uterine smooth muscle cells (ELT-3 cells). We found that ET-1 exerted a more potent mitogenic effect in ELT-3 cells than in normal myometrial cells, as indicated by the increase in [3H]thymidine incorporation, cell number, and bromodeoxyuridine incorporation. The ET-1 was more efficient than platelet-derived growth factor and epidermal growth factor to stimulate proliferation. The ET-1-mediated cell proliferation was inhibited in the presence of U0126, a specific inhibitor of (mitogen-activated protein kinase ERK kinase), indicating that extracellular signal-regulated kinase (ERK) activation is involved. Additionally, ET-1 induced the activation of phospholipase (PL) D, leading to the synthesis of phosphatidic acid (PA). The ET-1-induced activation of PLD was twofold higher in ELT-3 cells compared to that in normal cells. The two cell types expressed mRNA for PLD1a and PLD2, whereas PLD1b was expressed only in ELT-3 cells. The exposure of cells to butan-1-ol reduced ET-1-mediated production of PA by PLD and partially inhibited ERK activation and DNA synthesis. Addition of exogenous PLD or PA in the medium reproduced the effect of ET-1 on ERK activation and cell proliferation. Collectively, these data indicate that ET-1 is a potent mitogenic factor in ELT-3 cells via a signaling pathway involving a PLD-dependent activation of ERK. This highlights the potential role of ET-1 in the development of uterine leiomyoma, and it reinforces the role of PLD in tumor growth.
Robin
Philippe
P
Laboratoire de signalisation et régulations cellulaires, IBBMC, CNRS UMR 8619, Bat 430 Université Paris Sud, 91 405 Orsay Cedex, France.
Chouayekh
Sondes
S
Bole-Feysot
Christine
C
Leiber
Denis
D
Tanfin
Zahra
Z
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D007889:Leiomyoma / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000378:metabolism; D010739:Phospholipase D / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014594:Uterine Neoplasms / Q000378:metabolism* / Q000473:pathology
D002070:Butadienes; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009570:Nitriles; D010712:Phosphatidic Acids; C113580:U 0126; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1