title: Activation of the MAPK/ERK Cell-Signaling Pathway in Uterine Smooth Muscle Cells of Women With Adenomyosis.
abstract: We investigated whether the myometrium might be intrinsically different in women with adenomyosis. We studied whether the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPKs/ERKs) and phosphoinositide 3-kinase/mammalian target of rapamycin/AKT (PI3K/mTOR/AKT) cell-signaling pathways, implicated in the pathogenesis of endometriosis, might also be activated in uterine smooth muscle cells (uSMCs) of women with adenomyosis and measured the production of reactive oxygen species (ROS), proinflammatory mediators that modulate cell proliferation and have been shown to activate the MAPK/ERK pathway in endometriosis. The uSMC cultures were derived from myometrium biopsies obtained during hysterectomy or myomectomy in women with adenomyosis and controls with leiomyoma. Proliferation of uSMCs and in vitro activation of the MAPK/ERK cell-signaling pathway were increased in women with adenomyosis compared to controls. The activation of the PI3K/mTOR/AKT pathway was not significant. The ROS production and ROS detoxification pathways were not different between uSMCs of women with adenomyosis and controls suggesting an ROS-independent activation of the MAPK/ERK pathway. Our results also provide evidence that protein kinase inhibitors and the rapanalogue temsirolimus can control proliferation of uSMCs in vitro suggesting an implication of the MAPK/ERK and the PI3K/mTOR/AKT pathways in proliferation of uSMCs in women with adenomyosis and leiomyomas.
authors.affiliation: Department of Gynaecology Obstetrics II and Reproductive Medicine, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Paris, France Department of Development, Reproduction and Cancer, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, CNRS (UMR 8104), Paris, France. Department of Gynaecology and Obstetrics, Unit for Reproductive Medicine and Gynaecological Endocrinology, University Hospitals of Geneva and the Faculty of Medicine of the Geneva University, Geneva, Switzerland Laboratory of Immunology, Groupe Hospitalier Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Streuli
authors.affiliation: Department of Gynaecology Obstetrics II and Reproductive Medicine, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Paris, France Department of Development, Reproduction and Cancer, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, CNRS (UMR 8104), Paris, France. Laboratory of Immunology, Groupe Hospitalier Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pietro
authors.initials: P
authors.lastname: Santulli
authors.affiliation: Department of Development, Reproduction and Cancer, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, CNRS (UMR 8104), Paris, France. Laboratory of Immunology, Groupe Hospitalier Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chouzenoux
authors.affiliation: Department of Gynaecology Obstetrics II and Reproductive Medicine, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Paris, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Chapron
authors.affiliation: Department of Development, Reproduction and Cancer, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, CNRS (UMR 8104), Paris, France. Laboratory of Immunology, Groupe Hospitalier Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris, France frederic.batteux@cch.aphp.fr batteux@gmail.com.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D062788:Adenomyosis / Q000201:enzymology* / Q000473:pathology; D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009215:Myometrium / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: MAPK/ERK pathway; PI3K/mTOR/AKT pathway; adenomyosis; leiomyomas