Mechanisms of Hormone Action

Contribution of Phospholipase D in Endothelin-1-Mediated Extracellular Signal-Regulated Kinase Activation and Proliferation in Rat Uterine Leiomyoma Cells

Abstract
Endothelin-1 (ET-1) is a mitogenic factor in numerous cell types including rat myometrial cells. In this 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, increase in cell number and bromodeoxyuridine incorporation. ET-1 was more efficient than PDGF and EGF to stimulate proliferation. ET-1-mediated cell proliferation was inhibited in the presence of U0126, a specific inhibitor of MEK, indicating that ERK activation is involved. ET-1 also induced the activation of phospholipase D (PLD) leading to the synthesis of phosphatidic acid (PA). ET-1-induced PLD activation was 2 fold higher in ELT-3 cells compared to 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 PA production 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 indicated 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 implication of ET-1 in the development of uterine leiomyoma and reinforces the role of PLD in tumor growth.

Key words: Female Reproductive Tract • Growth factors • Kinases • Signal transduction • Uterus

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