Androgen Receptor Mediates Non-genomic Activation of Phosphatidylinositol 3-OH Kinase in Androgen-sensitive Epithelial Cells*

Androgens are known to modulate many cellular processes such as cell growth and survival by binding to the androgen receptor (AR) and activating the transcription of target genes. Recent data suggested that AR can also mediate non-transcriptional actions outside the nucleus in addition to its ligand-inducible transcription factor function. Here, we describe a transcription-independent activation of the phosphatidylinositol 3-OH kinase (PI3-K) signaling pathway by androgens. Using non-transformed androgen-sensitive epithelial cells, we show that androgens enhance the PI3-K activity by promoting accumulation of phosphoinositide-3-P phospholipids in vitro. This activation is found in conjunction with an increased time-dependent phosphorylation of the downstream kinase AKT/protein kinase B on both Ser473 and Thr308 residues. Hormone-stimulated phosphorylation of AKT requires AR since incubation with the anti-androgen bicalutamide completely abolishes the androgen-stimulated AKT phosphorylation. Accordingly, we show that androgens increase AKT phosphorylation level in prostatic carcinoma PC3 cells only once they have been transfected with AR. Downstream, androgens enhance phosphorylation of transcription factor FKHR (Forkhead in rhabdomyosarcoma)-L1 and proapoptotic Bad protein and promote cell survival as they can counteract an apoptotic process. We also report that non-genomic effects of androgens are based on direct interaction between AR and the p85α regulatory subunit of class I(A) PI3-K. Together, these novel findings point out an important and physiologically relevant link between androgens and the PI3-K/AKT signaling pathway in governing cell survival.

• Publication year

  2004

• Venue

  Journal of Biological Chemistry

• Publication date

  2004-04-09

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.M306143200PMID 14668339
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• AKT-Independent Protection of Prostate Cancer Cells from Apoptosis Mediated through Complex Formation between the Androgen Receptor and FKHR

  2003cited by this paper
• The phosphoinositide 3-kinase pathway.

  2002cited by this paper
• Androgen receptor expression is regulated by the phosphoinositide 3-kinase/Akt pathway in normal and tumoral epithelial cells.

  2002cited by this paper
• Paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system

  2001cited by this paper
• The Classical Progesterone Receptor Associates with p42 MAPK and Is Involved in Phosphatidylinositol 3-Kinase Signaling inXenopus Oocytes*

  2001cited by this paper
• Estrogen Induces the Akt-dependent Activation of Endothelial Nitric-oxide Synthase in Vascular Endothelial Cells*

  2001cited by this paper
• Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K.

  2001cited by this paper
• Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases.

  2001cited by this paper
• Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity.

  2001cited by this paper
• Increased insulin sensitivity in mice lacking p85β subunit of phosphoinositide 3-kinase

  2001cited by this paper
• Estrogen receptor alpha and endothelial nitric oxide synthase are organized into a functional signaling module in caveolae.

  2000cited by this paper
• Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase

  2000cited by this paper
• Multiple actions of steroid hormones--a focus on rapid, nongenomic effects.

  2000cited by this paper
• Specificity and mechanism of action of some commonly used protein kinase inhibitors.

  2000cited by this paper
• Acquisition of androgen-mediated expression of mouse vas deferens protein (MVDP) gene in cultured epithelial cells and in vas deferens during postnatal development.

  2000cited by this paper
• The classical progesterone receptor mediates Xenopus oocyte maturation through a nongenomic mechanism.

  2000cited by this paper
• Steroid‐induced androgen receptor–oestradiol receptor β–Src complex triggers prostate cancer cell proliferation

  2000cited by this paper
• Specificity and mechanism of action of some commonly used protein kinase inhibitors

  2000cited by this paper
• Estrogen Receptor a and Endothelial Nitric Oxide Synthase Are Organized Into a Functional Signaling Module in Caveolae

  2000cited by this paper
• Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen.

  1999cited by this paper
• Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.

  1999cited by this paper
• Structural and Biochemical Evaluation of the Interaction of the Phosphatidylinositol 3-Kinase p85α Src Homology 2 Domains with Phosphoinositides and Inositol Polyphosphates*

  1999cited by this paper
• Rapid signalling by androgen receptor in prostate cancer cells

  1999cited by this paper
• Estrogen: mechanisms for a rapid action in CA1 hippocampal neurons.

  1999cited by this paper
• Phosphoinositide kinases.

  1998cited by this paper
• Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross‐talk with estrogen receptor

  1998cited by this paper
• Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha.

  1997cited by this paper
• PI3K: downstream AKTion blocks apoptosis.

  1997cited by this paper
• Growth factors as mediators of androgen action during male urogenital development

  1996cited by this paper
• Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L)

  1996cited by this paper
• Growth factor-dependent survival of rodent fibroblasts requires phosphatidylinositol 3-kinase but is independent of pp70S6K activity.

  1996cited by this paper
• Exportation of mouse vas deferens protein, a protein without a signal peptide, from mouse vas deferens epithelium: a model of apocrine secretion.

  1995cited by this paper
• Emerging diversities in the mechanism of action of steroid hormones.

  1995cited by this paper
• The nuclear receptor superfamily: the second decade.

  1995cited by this paper
• A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signal transduction.

  1995cited by this paper
• PI 3‐kinase is a dual specificity enzyme: autoregulation by an intrinsic protein‐serine kinase activity.

  1994cited by this paper
• Activation of phosphoinositide 3-kinase is required for PDGF-stimulated membrane ruffling.

  1994cited by this paper
• cDNA cloning of a novel 85 kd protein that has SH2 domains and regulates binding of PI3-kinase to the PDGF beta-receptor.

  1991cited by this paper
• Activation of phosphatidylinositol 3-kinase by insulin.

  1990cited by this paper
• The human androgen receptor: domain structure, genomic organization and regulation of expression.

  1989cited by this paper
• The steroid and thyroid hormone receptor superfamily.

  1988cited by this paper
• Identification of a new class of steroid hormone receptors

  1988cited by this paper

• Osteoporosis After Menopause and After Drug Therapy: The Molecular Mechanism of Bone Loss and Its Treatment

  2026cites this paper
• TFAM Loss Induces Oxidative Stress and Divergent Phenotypes in Glioblastoma Metabolic Subtypes

  2025cites this paper
• Androgens as the “old age stick” in skeletal muscle

  2025cites this paper
• Liver Androgen Receptor Knockout Attenuates High-Fructose Diet-Induced Glucose Dysregulation in Female Mice.

  2025cites this paper
• Proteogenomic Characterization of Triple-Negative Apocrine Carcinoma Reveals Molecular Features of Progression and Chemotherapy Response

  2025cites this paper
• Sex hormone receptor signaling networks drive pancreatic solid-pseudopapillary neoplasm pathogenesis and therapy

  2025cites this paper
• Proteomics characterization of triple-negative apocrine carcinoma reveals molecular features of progression and chemotherapy response

  2025cites this paper
• Untangling the role of tau in sex hormone responsive cancers: lessons learnt from Alzheimer's disease

  2024cites this paper
• A comprehensive review on the effects of sex hormones on chemotherapy-induced cardiotoxicity: are they lucrative or unprofitable?

  2024cites this paper
• Targeting CDK7 enhances the antitumor efficacy of enzalutamide in androgen receptor-positive triple-negative breast cancer by inhibiting c-MYC-mediated tumorigenesis.

  2024cites this paper
• Digital spatial profiling identifies the tumor center as a topological niche in prostate cancer characterized by an upregulation of BAD

  2024cites this paper
• Litopenaeus vannamei heat shock protein 90 (LvHSP90) interacts with white spot syndrome virus protein, WSSV322, to modulate hemocyte apoptosis during viral infection.

  2024cites this paper
• The roles of sex hormones in the pathophysiology of age‐related sarcopenia and frailty

  2024cites this paper
• Liver Androgen Receptor Knockout Improved High-fat Diet Induced Glucose Dysregulation in Female Mice But Not Male Mice

  2024cites this paper
• The interplay between androgens and the immune response in polycystic ovary syndrome

  2023cites this paper
• Dissecting the effects of androgen deprivation therapy on cadherin switching in advanced prostate cancer: A molecular perspective

  2023influential citation
• Cancer Stem Cells and Androgen Receptor Signaling: Partners in Disease Progression

  2023cites this paper
• The impact of PIK3R1 mutations and insulin-PI3K-glycolytic pathway regulation in prostate cancer.

  2022cites this paper
• Molecular Regulation of Androgen Receptors in Major Female Reproductive System Cancers

  2022cites this paper
• Gender Differential Expression of AR/miR-21 Signaling Axis and Its Protective Effect on Renal Ischemia-Reperfusion Injury

  2022cites this paper
• Integration of androgen hormones in endometrial cancer biology.

  2022cites this paper
• Androgens regulate tau phosphorylation through PI3K-Akt-GSK3β signaling.

  2022cites this paper
• Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease

  2021cites this paper
• Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

  2021cites this paper
• On the role of sex steroids in biological functions by classical and non-classical pathways. An update

  2021influential citation
• Proximity-dependent Mapping of the Androgen Receptor Identifies Kruppel-like Factor 4 as a Functional Partner

  2021cites this paper
• Role of PI3K-AKT-mTOR Pathway as a Pro-Survival Signaling and Resistance-Mediating Mechanism to Therapy of Prostate Cancer

  2021cites this paper
• DHT causes liver steatosis via transcriptional regulation of SCAP in normal weight female mice

  2021cites this paper
• Non-genomic signaling of steroid receptors in cancer.

  2021cites this paper
• Androgen/Androgen Receptor Signaling in Ovarian Cancer: Molecular Regulation and Therapeutic Potentials

  2021cites this paper
• The Pathological Effect of Exogenous Testosterone on the Male Genital Organs of Rat

  2020cites this paper
• Pathophysiological effects of androgens on the female vascular system

  2020cites this paper
• In silico docking of phytocompounds to identify potent inhibitors of signaling pathways involved in prostate cancer

  2020cites this paper
• Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

  2020cites this paper
• Cellular growth factors as prospective therapeutic targets for combination therapy in androgen independent prostate cancer (AIPC).

  2020cites this paper
• Resistance to second generation antiandrogens in prostate cancer: pathways and mechanisms

  2020cites this paper
• The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

  2020cites this paper
• Role of Endoplasmic Reticulum Stress and Autophagy in Tumor Drug Resistance

  2020influential citation
• Androgen receptor: A promising therapeutic target in breast cancer

  2019cites this paper
• Steroid Receptor Signallings as Targets for Resveratrol Actions in Breast and Prostate Cancer

  2019influential citation
• Androgen Receptor Dependence.

  2019cites this paper
• Advances in understanding mechanisms of long-term sperm storage-the soft-shelled turtle model.

  2019cites this paper
• Analyse protéomique des réseaux de signalisation du récepteur aux androgènes modulés par l'Enzalutamide dans le cancer de la prostate résistant à la castration

  2019influential citation
• Involvement of sex hormonal regulation of K+ channels in electrophysiological and contractile functions of muscle tissues.

  2019cites this paper
• Hormone-Responsive Cancers

  2019cites this paper
• Non-nuclear AR Signaling in Prostate Cancer

  2019influential citation
• Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan.

  2018influential citation
• Androgenic signaling systems and their role in behavioral evolution.

  2018cites this paper
• Selective Androgen Receptor Modulator, YK11, Up-Regulates Osteoblastic Proliferation and Differentiation in MC3T3-E1 Cells.

  2018cites this paper
• LXRs, SHP, and FXR in Prostate Cancer: Enemies or Ménage à Quatre With AR?

  2018cites this paper
• Rôle du récepteur des androgènes dans les communications cellulaires au sein du cancer de la prostate

  2018cites this paper
• Non-Genomic Actions of the Androgen Receptor in Prostate Cancer

  2017influential citation
• Integrating insulin-like growth factor 1 and sex hormones into neuroprotection: Implications for diabetes

  2017cites this paper
• Extranuclear partners of androgen receptor: at the crossroads of proliferation, migration, and neuritogenesis

  2017influential citation
• Low-Dose Dihydrotestosterone Drives Metabolic Dysfunction via Cytosolic and Nuclear Hepatic Androgen Receptor Mechanisms

  2017cites this paper
• Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXRα

  2017cites this paper
• Androgen interacts with exercise through the mTOR pathway to induce skeletal muscle hypertrophy

  2017cites this paper
• Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease.

  2017cites this paper
• Sex hormonal regulation of cardiac ion channels in drug-induced QT syndromes.

  2016cites this paper
• Androgen receptor-mediated growth suppression and apoptosis of human prostate epithelial cells

  2016cites this paper
• Testosterone Antagonizes Doxorubicin‐Induced Senescence of Cardiomyocytes

  2016cites this paper
• Hydroxyflutamide affects connexin 43 via the activation of PI3K/Akt-dependent pathway but has no effect on the crosstalk between PI3K/Akt and ERK1/2 pathways at the Raf-1 kinase level in primary rat Sertoli cells.

  2016cites this paper
• Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification

  2016cites this paper
• Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance

  2016cites this paper
• Androgen-related sperm storage in oviduct of Chinese Soft-Shelled Turtle in vivo during annual cycle

  2016cites this paper
• Roles of the Androgen--Androgen Receptor System in Vascular Angiogenesis.

  2016cites this paper
• The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance.

  2016cites this paper
• A Signaling Network Controlling Androgenic Repression of c-Fos Protein in Prostate Adenocarcinoma Cells*

  2016cites this paper
• Androgen Receptor-Mediated Genomic Androgen Action Augments Ischemia-Induced Neovascularization.

  2016cites this paper
• In Vivo Evidence of the Androgen Receptor in Association With Myometrial Cell Proliferation and Apoptosis

  2016cites this paper
• Androgen synthesis, metabolism and action in the developing ovarian follicle

  2016cites this paper
• Targets to treat androgen excess in polycystic ovary syndrome

  2015cites this paper
• Prostate cancer stem cells: the role of androgen and estrogen receptors

  2015cites this paper
• Evaluation de l’activité oestrogenique de contaminants et développement d’un bio-récepteur d’affinité pour la détection d’une xéno-hormone

  2014cites this paper
• Chapter 29 – Hormone Responsive Cancers

  2014cites this paper
• Ligand-independent androgen receptors promote ovarian teratocarcinoma cell growth by stimulating self-renewal of cancer stem/progenitor cells.

  2014cites this paper
• Skeletal Muscle Tissue Engineering: Methods to Form Skeletal Myotubes and Their Applications

  2014cites this paper
• Hic-5 influences genomic and non-genomic actions of the androgen receptor in prostate myofibroblasts.

  2014cites this paper
• Androgens and the molecular regulation of skeletal muscle mass

  2014cites this paper
• Hormone-Resistant ProstateCancerCells and ConferResistance toApoptosis

  2013influential citation
• Androgen deprivation and androgen receptor competition by bicalutamide induce autophagy of hormone‐resistant prostate cancer cells and confer resistance to apoptosis

  2013influential citation
• Androgen Receptor Promotes Sex-Independent Angiogenesis in Response to Ischemia and Is Required for Activation of Vascular Endothelial Growth Factor Receptor Signaling

  2013cites this paper
• Influence of Epilobium angustifolium extract on 5α-reductase type 2 and MAPK3 kinase gene expression in rats prostates

  2013cites this paper
• Involvement of androgens in ovarian health and disease.

  2013cites this paper
• SRC kinase mRNA transcription changes in testosterone-induced rat ventral prostate lobes under the influence of Epilobium angustifolium extract

  2013cites this paper
• Evidence of mTOR Activation by an AKT-Independent Mechanism Provides Support for the Combined Treatment of PTEN-Deficient Prostate Tumors with mTOR and AKT Inhibitors.

  2012cites this paper
• Androgen receptor antagonists: a patent review (2008 – 2011)

  2012influential citation
• Award Number: W81XWH-09-1-0137 TITLE: Protein Phosphatase 2A Signaling in Human Prostate Cancer

  2012cites this paper
• Role of Androgens and Androgen Receptor in Prostate Cancer: Genomic and Non-Genomic Actions

  2012cites this paper
• The Impact of Point Mutations in the Human Androgen Receptor: Classification of Mutations on the Basis of Transcriptional Activity

  2012cites this paper
• Old issues and new perspectives on prostate cancer hormonal therapy: the molecular substratum

  2012cites this paper
• Activation of PKR/eIF2α signaling cascade is associated with dihydrotestosterone‐induced cell cycle arrest and apoptosis in human liver cells

  2012influential citation
• Dieta hiperlipídica e envelhecimento modificam a sensibilidade à insulina e a expressão das proteinas relacionadas à via intracelular da insulina em hipotálamo de camundongos fêmeas.

  2012cites this paper
• Mechanisms of Signal Transduction in Prostate Cancer: The Role of PI3-Kinase Pathway in Androgen Action

  2012cites this paper
• Modulation of Protein Phosphatase 2A Activity Alters Androgen-Independent Growth of Prostate Cancer Cells: Therapeutic Implications

  2011cites this paper
• Integrins Regulate Microtubule Nucleating Activity of Centrosome through Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase/Extracellular Signal-regulated Kinase (MEK/ERK) Signaling*

  2011cites this paper
• PI3K/mTOR signaling regulates prostatic branching morphogenesis.

  2011cites this paper
• Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions

  2011cites this paper
• Sperm storage in the female reproductive tract of Scotophilus heathii: Role of androgen

  2011cites this paper
• Hormone depletion-insensitivity of prostate cancer cells is supported by the AR without binding to classical response elements.

  2011cites this paper