Activation of the MAPK/ERK Cell-Signaling Pathway in Uterine Smooth Muscle Cells of Women With Adenomyosis

Reprod Sci. 2015 Dec;22(12):1549-60. doi: 10.1177/1933719115589410. Epub 2015 Jun 11.


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.

Keywords: MAPK/ERK pathway; PI3K/mTOR/AKT pathway; adenomyosis; leiomyomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomyosis / enzymology*
  • Adenomyosis / pathology
  • Adult
  • Antioxidants / pharmacology
  • Case-Control Studies
  • Cell Proliferation* / drug effects
  • Cells, Cultured
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Humans
  • Inflammation Mediators / metabolism
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology
  • Myometrium / drug effects
  • Myometrium / enzymology*
  • Myometrium / pathology
  • Phosphatidylinositol 3-Kinase / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction* / drug effects
  • TOR Serine-Threonine Kinases / metabolism


  • Antioxidants
  • Inflammation Mediators
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases