title: Androgen receptor drives cellular senescence.
abstract: The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor.
authors.affiliation: Urology Department, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Mirochnik
authors.forename: Dorina
authors.initials: D
authors.lastname: Veliceasa
authors.forename: Latanya
authors.initials: L
authors.lastname: Williams
authors.forename: Kelly
authors.initials: K
authors.lastname: Maxwell
authors.forename: Alexander
authors.initials: A
authors.lastname: Yemelyanov
authors.forename: Irina
authors.initials: I
authors.lastname: Budunova
authors.forename: Olga V
authors.initials: OV
authors.lastname: Volpert
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000071156:Promyelocytic Leukemia Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D059002:Androgen Receptor Antagonists; C081876:CKAP4 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; D008565:Membrane Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D017382:Reactive Oxygen Species; D011944:Receptors, Androgen; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D005485:Flutamide; D058570:TOR Serine-Threonine Kinases