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• Zengerling, F
• Streicher, W
• Schrader, A
• Schrader, M
• Nitzsche, B
• Cronauer, M
• Höpfner, M
• [+] on Google Scholar
• Zengerling, F
• Streicher, W
• Schrader, A
• Schrader, M
• Nitzsche, B
• Cronauer, M
• Höpfner, M
• [+] on PubMed
• Zengerling, F
• Streicher, W
• Schrader, A
• Schrader, M
• Nitzsche, B
• Cronauer, M
• Höpfner, M

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Int. J. Mol. Sci. 2012, 13(9), 11530-11542; doi:10.3390/ijms130911530

Article

Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

Friedemann Zengerling ^1,2,†,* , Wolfgang Streicher ^3,† , Andres J. Schrader ¹ , Mark Schrader ¹ , Bianca Nitzsche ² , Marcus V. Cronauer ¹  and Michael Höpfner ²

¹ Department of Urology, Ulm University, Ulm 89075, Germany ² Department of Physiology, Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin 14195, Germany ³ Institute of General Zoology and Endocrinology, Ulm University, Ulm 89069, Germany ^† These authors contributed equally to this work.

* Author to whom correspondence should be addressed.

Received: 7 August 2012; in revised form: 5 September 2012 / Accepted: 6 September 2012 / Published: 14 September 2012

(This article belongs to the Special Issue Advances in Molecular Oncology)

Download PDF Full-Text [471 KB, uploaded 14 September 2012 11:34 CEST]

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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