title: Membrane androgen receptor down-regulates c-src-activity and beta-catenin transcription and triggers GSK-3beta-phosphorylation in colon tumor cells.
abstract: OBJECTIVE
  Functional membrane androgen receptors (mARs) have recently been described in colon tumor cells and tissues. Their activation by specific testosterone albumin conjugates (TAC) down-regulates the PI-3K/Akt pro-survival signaling and triggers potent pro-apoptotic responses both, in vitro and in vivo. The present study explored the mAR-induced regulation of gene products implicated in the tumorigenic activity of Caco2 colon cancer cells.
  
  
  METHODS
  In Caco2 human colon cancer cells transcript levels were determined by RT-PCR, protein abundance and phosphorylation by Western blotting and confocal microscopy, as well as cytoskeletal architecture by confocal microscopy.
  
  
  RESULTS
  We report time dependent significant decrease in Tyr-416 phosphorylation of c-Src upon mAR activation. In line with the reported late down-regulation of the PI-3K/Akt pathway in testosterone-treated colon tumors, GSK-3beta was phosphorylated at Tyr-216 after long term stimulation of the cells with TAC, a finding supporting the role of this kinase to promote apoptosis. PCR analysis revealed significant decrease of beta-catenin and cyclin D1 transcript levels following TAC treatment. Moreover, confocal laser scanning microscopic analysis disclosed co-localization of beta-catenin with actin cytoskeleton. It is thus conceivable that beta-catenin may participate in the reported modulation of cytoskeletal dynamics in mAR stimulated Caco2 cells.
  
  
  CONCLUSIONS
  Our results provide strong evidence that mAR activation regulates late expression and/or activity of the tumorigenic gene products c-Src, GSK-3beta, and beta-catenin thus facilitating the pro-apoptotic response in colon tumor cells.
authors.affiliation: Department of Physiology, University of Tübingen, Germany.
authors.forename: Shuchen
authors.initials: S
authors.lastname: Gu
authors.forename: Sabina
authors.initials: S
authors.lastname: Honisch
authors.forename: Michalis
authors.initials: M
authors.lastname: Kounenidakis
authors.forename: Saad
authors.initials: S
authors.lastname: Alkahtani
authors.forename: Saud
authors.initials: S
authors.lastname: Alarifi
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Alevizopoulos
authors.forename: Christos
authors.initials: C
authors.lastname: Stournaras
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D000418:Albumins / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D016391:Genes, src / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013739:Testosterone / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000418:Albumins; D011944:Receptors, Androgen; D051176:beta Catenin; D013739:Testosterone; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3