title: Effects of sorafenib on C-terminally truncated androgen receptor variants in human prostate cancer cells.
abstract: Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD). Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.
authors.affiliation: Department of Urology, Ulm University, Ulm 89075, Germany.|Department of Physiology, Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin 14195, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Zengerling
authors.affiliation: Institute of General Zoology and Endocrinology, Ulm University, Ulm 89069, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Streicher
authors.affiliation: Department of Urology, Ulm University, Ulm 89075, Germany.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Schrader
authors.affiliation: Department of Urology, Ulm University, Ulm 89075, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Schrader
authors.affiliation: Department of Physiology, Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin 14195, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Nitzsche
authors.affiliation: Department of Urology, Ulm University, Ulm 89075, Germany.
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Cronauer
authors.affiliation: Department of Physiology, Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin 14195, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Höpfner
mesh_terms: D000728:Androgens / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen; D009536:Niacinamide; D000077157:Sorafenib; D046988:Proteasome Endopeptidase Complex
keywords: castration resistant prostate cancer; sorafenib; truncated androgen receptor variants