title: Targeting leiomyomas with all-trans-retinoic acid at phosphoinositide 3-kinase pathway suppression: Effective roles of β-catenin and of signaling interactions.
abstract: OBJECTIVE
  Leiomyomas, monoclonal tumors developed by the transformation of myometrium somatic stem cells, are a major health concern that can severely impair quality of life. Pathological alterations of signaling pathways have been recognized as a key feature in a variety of human diseases. Our objective was to analyze treatment with all-trans-retinoic acid (ATRA) by suppression of the phosphoinositide 3-kinase (PI3K) pathway on growth, signaling pattern and interactions among PI3K/B-cell lymphoma 2 (Bcl2)/retinol leiomyoma proteins.
  
  
  METHODS
  Cultures of paired myometrium and leiomyoma cells from premenopausal women undergoing hysterectomy were collected. Western blot and analysis of variance were used for analysis.
  
  
  RESULTS
  Significant differences were detected between treatment with ATRA alone or with LY294002 (a PI3K growth suppressor) in response to treatment and among cell samples and cell numbers. Leiomyoma cells were less affected. Immunochemical analysis of signaling patterns demonstrated that treatments affected most of the examined protein levels differently. Significant differences between the cell type responses to treatment in pyruvate phosphate dikinase 1 (pPDK1), Bad and pβ-catenin levels were identified. The pβ-catenin level showed highly significant interaction between response to treatment and cell type.
  
  
  CONCLUSIONS
  ATRA treatment on PI3K pathway suppression significantly affected growth, signaling pattern and interactions among PI3K/Bcl2/retinol proteins involved in the growth, survival and apoptosis of leiomyomas. Interpretation of our results suggests that increasing knowledge of the role of signaling interplay in the pathogenesis of leiomyomas may present an opportunity to use specific signal transduction inhibitors for treating and preventing this disorder.
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah Medical Center, Jerusalem, Israel.|Laboratory of Experimental Surgery, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Friedman
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Asher
authors.initials: A
authors.lastname: Shushan
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Nathan
authors.initials: N
authors.lastname: Rojansky
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Shveiky
authors.affiliation: Laboratory of Experimental Surgery, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Rubina
authors.initials: R
authors.lastname: Levitzki
authors.affiliation: Israel National Skin Bank, Hadassah Medical Center, Jerusalem, Israel.|Laboratory of Experimental Surgery, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Malka
authors.initials: M
authors.lastname: Chaouat
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah Medical Center, Jerusalem, Israel. h.benbassat@gmail.com.|Israel National Skin Bank, Hadassah Medical Center, Jerusalem, Israel. h.benbassat@gmail.com.
authors.forename: Hannah
authors.initials: H
authors.lastname: Ben-Bassat
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D005260:Female; D006801:Humans; D007044:Hysterectomy; D007889:Leiomyoma / Q000188:drug therapy / Q000378:metabolism*; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017697:Premenopause; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D002867:Chromones; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014212:Tretinoin; D051025:bcl-Associated Death Protein; D051176:beta Catenin; C494819:BAD protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: Apoptosis; PI3K/retinol/β-catenin/BCL2; fibroids; growth survival; signaling interactions; signaling pathways