title: MED15 overexpression in prostate cancer arises during androgen deprivation therapy via PI3K/mTOR signaling.
abstract: Androgen deprivation therapy (ADT) is the main therapeutic option for advanced prostate cancer (PCa). After initial regression, most tumors develop into castration-resistant PCa (CRPC). Previously, we found the Mediator complex subunit MED15 to be overexpressed in CRPC and to correlate with clinical outcome. Therefore, we investigated whether MED15 is implicated in the signaling changes taking place during progression to CRPC. Immunohistochemistry (IHC) for MED15 on matched samples from the same patients before and after ADT reveals significantly increased MED15 expression after ADT in 72%. A validation cohort comprising samples before and after therapy confirmed our observations. Protein analysis for pAKT and pSMAD3 shows that MED15 correlates with PI3K and TGFß activities, respectively, and that hyper-activation of both pathways simultaneously correlates with highest levels of MED15. We further show that MED15 protein expression increases in LNCaP cells under androgen deprivation, and via EGF mediated PI3K activation. PI3K/mTOR and TGFß-receptor inhibition results in decreased MED15 expression. MED15 knockdown reduces LNCaP cell viability and induces apoptosis during androgen deprivation, while cell cycle is not affected. Collectively, MED15 overexpression arises during ADT via hyper-activation of PI3K/mTOR signaling, thus MED15 may serve as a predictive marker for response to PI3K/mTOR inhibitors. Furthermore, MED15 is potentially a therapeutic target for the treatment of CRPC.
authors.affiliation: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Offermann
authors.affiliation: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany.
authors.forename: Ignacija
authors.initials: I
authors.lastname: Vlasic
authors.affiliation: Department of Urology, University Hospital Bonn, Bonn, Germany.|Section of Prostate Cancer Research, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.|Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.
authors.forename: Isabella
authors.initials: I
authors.lastname: Syring
authors.affiliation: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany.
authors.forename: Wenzel
authors.initials: W
authors.lastname: Vogel
authors.affiliation: Institute for Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Ruiz
authors.affiliation: Department of Urology, St. Claraspital, Basel, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Zellweger
authors.affiliation: Department of Urology, University Hospital Basel, Basel, Switzerland.
authors.forename: Cyrill A
authors.initials: CA
authors.lastname: Rentsch
authors.affiliation: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hagedorn
authors.affiliation: Core Facility Fluorescence Cytometry, Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Behrends
authors.affiliation: Section of Prostate Cancer Research, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.|Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Nowak
authors.affiliation: Department of Urology, University Hospital Luebeck, Luebeck, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Merseburger
authors.affiliation: Institute for Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.affiliation: Institute of Pathology, Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Kirfel
authors.affiliation: Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
authors.affiliation: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Adler
authors.affiliation: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; C416944:MED15 protein, human; D056892:Mediator Complex; D011944:Receptors, Androgen; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: MED15; PI3 kinase; androgen deprivation; castration-resistant prostate cancer; mediator complex