title: Rapid activation of FAK/mTOR/p70S6K/PAK1-signaling controls the early testosterone-induced actin reorganization in colon cancer cells.
abstract: Actin cytoskeleton reorganization initiated by testosterone conjugates through activation of membrane androgen receptors (mAR) has recently been reported in colon tumor cells. This mAR-induced actin reorganization was recognized as a critical initial event, controlling apoptosis and inhibiting cell migration. The present study addressed the molecular signaling regulating the rapid actin remodeling initiated upon testosterone-induced mAR activation in Caco2 colon tumor cells. We report early phosphorylation of the Focal Adhesion Kinase (FAK), followed by substantial early phosphorylation of mammalian target of rapamycin (mTOR), S6 kinase (p70S6K) and the actin regulating p21-activated kinase (PAK1). Pharmacological inhibition of FAK-sensitive phosphatidylinositide-3-kinase (PI-3K), a known element of mAR-signaling, fully abrogated the testosterone-induced actin reorganization and the activation of mTOR, p70S6K and PAK1. Similarly, inhibition of mTOR blocked p70S6K and PAK1 phosphorylation and actin remodeling. Pretreatment of the cells with the intracellular androgen receptor (iAR) antagonist flutamide or silencing iAR through siRNA did not influence mTOR phosphorylation and actin reorganization, indicating specific mAR-induced testosterone effects that are independent of iAR signaling. In conclusion, we demonstrate for the first time a new mAR-governed pathway involving FAK/PI-3K and mTOR/p70S6K/PAK1-cascade that regulates early actin reorganization in colon cancer cells.
authors: Department of Physiology, University of Tübingen, Germany.
authors: Shuchen
authors: S
authors: Gu
authors: Michalis
authors: M
authors: Kounenidakis
authors: Eva-Maria
authors: EM
authors: Schmidt
authors: Divija
authors: D
authors: Deshpande
authors: Saad
authors: S
authors: Alkahtani
authors: Saud
authors: S
authors: Alarifi
authors: Michael
authors: M
authors: Föller
authors: Konstantinos
authors: K
authors: Alevizopoulos
authors: Florian
authors: F
authors: Lang
authors: Christos
authors: C
authors: Stournaras
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects*; D000199:Actins / Q000378:metabolism*; D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D005485:Flutamide / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D012709:Serum Albumin / Q000737:chemistry; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013739:Testosterone / Q000737:chemistry / Q000494:pharmacology*; D054462:p21-Activated Kinases / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D059002:Androgen Receptor Antagonists; D005485:Flutamide; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D012709:Serum Albumin; D058570:TOR Serine-Threonine Kinases; D013739:Testosterone; D054462:p21-Activated Kinases; D054460:rho-Associated Kinases