title: The mTOR/AKT inhibitor temsirolimus prevents deep infiltrating endometriosis in mice.
abstract: Deep infiltrating endometriosis (DIE) is a particular clinical and histological entity of endometriosis responsible for chronic pelvic pain and infertility. Here we characterize the proliferative phenotype of DIE cells, to explore the cellular and molecular mechanisms that could explain their aggressive potential. In addition, the inhibition of mTOR/AKT pathway was tested, as a potential treatment of DIE. Included were 22 patients with DIE and 12 control patients without endometriosis. Epithelial and stromal cells were extracted from biopsies of eutopic endometrium and deep infiltrating endometriotic nodules from patients with DIE. Cell proliferation was determined by thymidine incorporation. Oxidative stress was assayed by spectrofluorometry. The ERK and mTOR/AKT pathways were analyzed in vitro by Western blot and for AKT in vivo in a mouse model of DIE. The proliferation rate of eutopic endometrial cells and of deep infiltrating endometriotic cells from DIE patients was higher than that of endometrial cells from controls. The hyperproliferative phenotype of endometriotic cells was associated with an increase in endogenous oxidative stress, and with activation of the ERK and mTOR/AKT pathways. mTOR/AKT inhibition by temsirolimus decreased endometriotic cell proliferation both in vitro and in vivo in a mouse model of DIE. Blocking the mTOR/AKT pathway offers new prospects for the treatment of DIE.
authors: Laboratory of Immunology, Paris Descartes University, Hospital Cochin, Paris, France.
authors: Mahaut
authors: M
authors: Leconte
authors: Carole
authors: C
authors: Nicco
authors: Charlotte
authors: C
authors: Ngô
authors: Christiane
authors: C
authors: Chéreau
authors: Sandrine
authors: S
authors: Chouzenoux
authors: Wioleta
authors: W
authors: Marut
authors: Jean
authors: J
authors: Guibourdenche
authors: Sylviane
authors: S
authors: Arkwright
authors: Bernard
authors: B
authors: Weill
authors: Charles
authors: C
authors: Chapron
authors: Bertrand
authors: B
authors: Dousset
authors: Frédéric
authors: F
authors: Batteux
mesh_terms: D000328:Adult; D000818:Animals; D001706:Biopsy; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004715:Endometriosis / Q000378:metabolism*; D004717:Endometrium / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D018384:Oxidative Stress; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D013050:Spectrometry, Fluorescence / Q000379:methods; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C401859:temsirolimus; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus