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Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells
Authors:Friedemann Zengerling  Wolfgang Streicher  Andres J Schrader  Mark Schrader  Bianca Nitzsche  Marcus V Cronauer  Michael H?pfner
Affiliation:1.Department of Urology, Ulm University, Ulm 89075, Germany; E-Mails: (A.J.S.); (M.S.); (M.V.C.);2.Department of Physiology, Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin 14195, Germany; E-Mails: (B.N.); (M.H.);3.Institute of General Zoology and Endocrinology, Ulm University, Ulm 89069, Germany; E-Mail:
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.
Keywords:sorafenib  truncated androgen receptor variants  castration resistant prostate cancer
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