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Effects of sorafenib on C-terminally truncated androgen receptor variants in human prostate cancer cells.

Zengerling F, Streicher W, Schrader AJ, Schrader M, Nitzsche B, Cronauer MV, Höpfner M - Int J Mol Sci (2012)

Bottom Line: In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Ulm University, Ulm 89075, Germany; E-Mails: ajschrader@gmx.de (A.J.S.); mark.schrader@uniklinik-ulm.de (M.S.); marcus.cronauer@uni-ulm.de (M.V.C.) ; Department of Physiology, Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin 14195, Germany; E-Mails: bianca.nitzsche@charite.de (B.N.); michael.hoepfner@charite.de (M.H.).

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.

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Sorafenib does not modulate subcellular distribution of AR and ARΔLBD in PCa cells. PC-3 cells were transfected with either pAR-t1EosFP or pEGFP-ARQ640X coding for green fluorescent AR-EosFP and ARQ640X-EGFP fusion proteins [17,21]. Cells were treated with sorafenib 5 μM (SORA) in the absence/presence of DHT (10 nM). Intracellular localization of AR-EosFP and ARΔLBD-EGFP was determined by fluorescence microscopy. (A) Effect of sorafenib on the subcellular distribution of the AR. Left panel: Fluorescence microscopy of AR-EosFP transfected cells. Right panel: Percentage of cells expressing cytoplasmic (black bars) or nuclear fluorescence (white bars), (a) untreated controls; (b) sorafenib; (c) Dihydrotestosterone (DHT); (d) sorafenib + DHT; (B) Effect of sorafenib on the subcellular distribution of the ARLBD. Left panel: Fluorescence microscopy of ARΔLBD-EGFP transfected cells. Right panel: Percentage of cells expressing cytoplasmic (black bars) or nuclear fluorescence (white bars); (e) untreated controls; (f) sorafenib.
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f4-ijms-13-11530: Sorafenib does not modulate subcellular distribution of AR and ARΔLBD in PCa cells. PC-3 cells were transfected with either pAR-t1EosFP or pEGFP-ARQ640X coding for green fluorescent AR-EosFP and ARQ640X-EGFP fusion proteins [17,21]. Cells were treated with sorafenib 5 μM (SORA) in the absence/presence of DHT (10 nM). Intracellular localization of AR-EosFP and ARΔLBD-EGFP was determined by fluorescence microscopy. (A) Effect of sorafenib on the subcellular distribution of the AR. Left panel: Fluorescence microscopy of AR-EosFP transfected cells. Right panel: Percentage of cells expressing cytoplasmic (black bars) or nuclear fluorescence (white bars), (a) untreated controls; (b) sorafenib; (c) Dihydrotestosterone (DHT); (d) sorafenib + DHT; (B) Effect of sorafenib on the subcellular distribution of the ARLBD. Left panel: Fluorescence microscopy of ARΔLBD-EGFP transfected cells. Right panel: Percentage of cells expressing cytoplasmic (black bars) or nuclear fluorescence (white bars); (e) untreated controls; (f) sorafenib.

Mentions: Besides its effects on AR-stability, various kinase inhibitors were shown to modulate the intracellular localization of the AR [21,24–26]. In consequence we wondered whether the multikinase inhibitor sorafenib is also able to modulate subcellular distribution of AR-molecules. Therefore, we transfected PC-3 cells with expression plasmids coding for green fluorescent AR- and ARQ640X-fusion proteins. As seen in Figure 4, sorafenib was unable to influence the subcellular distribution of AR as well as its c-terminally truncated ARΔLBD-counterpart ARQ640X.


Effects of sorafenib on C-terminally truncated androgen receptor variants in human prostate cancer cells.

Zengerling F, Streicher W, Schrader AJ, Schrader M, Nitzsche B, Cronauer MV, Höpfner M - Int J Mol Sci (2012)

Sorafenib does not modulate subcellular distribution of AR and ARΔLBD in PCa cells. PC-3 cells were transfected with either pAR-t1EosFP or pEGFP-ARQ640X coding for green fluorescent AR-EosFP and ARQ640X-EGFP fusion proteins [17,21]. Cells were treated with sorafenib 5 μM (SORA) in the absence/presence of DHT (10 nM). Intracellular localization of AR-EosFP and ARΔLBD-EGFP was determined by fluorescence microscopy. (A) Effect of sorafenib on the subcellular distribution of the AR. Left panel: Fluorescence microscopy of AR-EosFP transfected cells. Right panel: Percentage of cells expressing cytoplasmic (black bars) or nuclear fluorescence (white bars), (a) untreated controls; (b) sorafenib; (c) Dihydrotestosterone (DHT); (d) sorafenib + DHT; (B) Effect of sorafenib on the subcellular distribution of the ARLBD. Left panel: Fluorescence microscopy of ARΔLBD-EGFP transfected cells. Right panel: Percentage of cells expressing cytoplasmic (black bars) or nuclear fluorescence (white bars); (e) untreated controls; (f) sorafenib.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472761&req=5

f4-ijms-13-11530: Sorafenib does not modulate subcellular distribution of AR and ARΔLBD in PCa cells. PC-3 cells were transfected with either pAR-t1EosFP or pEGFP-ARQ640X coding for green fluorescent AR-EosFP and ARQ640X-EGFP fusion proteins [17,21]. Cells were treated with sorafenib 5 μM (SORA) in the absence/presence of DHT (10 nM). Intracellular localization of AR-EosFP and ARΔLBD-EGFP was determined by fluorescence microscopy. (A) Effect of sorafenib on the subcellular distribution of the AR. Left panel: Fluorescence microscopy of AR-EosFP transfected cells. Right panel: Percentage of cells expressing cytoplasmic (black bars) or nuclear fluorescence (white bars), (a) untreated controls; (b) sorafenib; (c) Dihydrotestosterone (DHT); (d) sorafenib + DHT; (B) Effect of sorafenib on the subcellular distribution of the ARLBD. Left panel: Fluorescence microscopy of ARΔLBD-EGFP transfected cells. Right panel: Percentage of cells expressing cytoplasmic (black bars) or nuclear fluorescence (white bars); (e) untreated controls; (f) sorafenib.
Mentions: Besides its effects on AR-stability, various kinase inhibitors were shown to modulate the intracellular localization of the AR [21,24–26]. In consequence we wondered whether the multikinase inhibitor sorafenib is also able to modulate subcellular distribution of AR-molecules. Therefore, we transfected PC-3 cells with expression plasmids coding for green fluorescent AR- and ARQ640X-fusion proteins. As seen in Figure 4, sorafenib was unable to influence the subcellular distribution of AR as well as its c-terminally truncated ARΔLBD-counterpart ARQ640X.

Bottom Line: In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Ulm University, Ulm 89075, Germany; E-Mails: ajschrader@gmx.de (A.J.S.); mark.schrader@uniklinik-ulm.de (M.S.); marcus.cronauer@uni-ulm.de (M.V.C.) ; Department of Physiology, Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin 14195, Germany; E-Mails: bianca.nitzsche@charite.de (B.N.); michael.hoepfner@charite.de (M.H.).

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.

Show MeSH
Related in: MedlinePlus