Limits...
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.

Show MeSH

Related in: MedlinePlus

Sorafenib inhibits androgen receptor (AR)-signalling in prostate cancer (PCa) cells. PC-3 cells were cotransfected with an AR-expression construct together with an AR-dependent (A) Prostate specific antigen (PSA) or (B) ARE(2x)-reporter plasmid. pRL-tk-LUC was co-transfected as an internal control for transfection efficiency. Reportergene activity after sorafenib treatment (SORA) was measured using a Dual-Luciferase Reporter Assay as recently described [17]. Results are expressed in percent transactivation of dihydrotestosterone (DHT)-treated cells which were set at 100%; *p < 0.05; **p < 0.01; ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-ijms-13-11530: Sorafenib inhibits androgen receptor (AR)-signalling in prostate cancer (PCa) cells. PC-3 cells were cotransfected with an AR-expression construct together with an AR-dependent (A) Prostate specific antigen (PSA) or (B) ARE(2x)-reporter plasmid. pRL-tk-LUC was co-transfected as an internal control for transfection efficiency. Reportergene activity after sorafenib treatment (SORA) was measured using a Dual-Luciferase Reporter Assay as recently described [17]. Results are expressed in percent transactivation of dihydrotestosterone (DHT)-treated cells which were set at 100%; *p < 0.05; **p < 0.01; ***p < 0.001.

Mentions: Recently, sorafenib was shown to target AR-signalling in LNCaP and castration resistant LNCaP-sublines (LNCaP-abl, LNCaP-IL6+, LNCaP-Bic) [15]. As LNCaP cells express a promiscuous full length AR (919 amino acids, point mutation in the LBD, T877A) [16], we analyzed the effects of sorafenib on AR-signalling in PC-3 cells transiently transfected with a wild type AR. As seen in Figure 1, sorafenib diminished transactivation of AR-dependent reportergene constructs (ARE(2x), PSA) in PC-3 cells. Inhibition was already significant for the PSA-reporter at a concentration of 2.5 μM (downregulation versus DHT-treated controls: 23% ± 11%, p = 0.034), reaching its maximum at 10 μM, (downregulation versus DHT-treated controls: 60% ± 10%, p < 0.001; Figure 1A). Inhibition of ARE(2x)-promoter construct was relatively weak but statistically significant at concentrations >5μM (downregulation versus DHT-treated controls at 7.5 μM, 22% ± 6%, p = 0.033) reaching its maximum at 10 μM (downregulation 32% ± 4%, p = 0.002; Figure 1B). The reportergene assays are in agreement with previous findings, showing a sorafenib-induced downregulation of prostate specific antigen (PSA) in LNCaP and castration resistant LNCaP sublines [15].


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 inhibits androgen receptor (AR)-signalling in prostate cancer (PCa) cells. PC-3 cells were cotransfected with an AR-expression construct together with an AR-dependent (A) Prostate specific antigen (PSA) or (B) ARE(2x)-reporter plasmid. pRL-tk-LUC was co-transfected as an internal control for transfection efficiency. Reportergene activity after sorafenib treatment (SORA) was measured using a Dual-Luciferase Reporter Assay as recently described [17]. Results are expressed in percent transactivation of dihydrotestosterone (DHT)-treated cells which were set at 100%; *p < 0.05; **p < 0.01; ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-ijms-13-11530: Sorafenib inhibits androgen receptor (AR)-signalling in prostate cancer (PCa) cells. PC-3 cells were cotransfected with an AR-expression construct together with an AR-dependent (A) Prostate specific antigen (PSA) or (B) ARE(2x)-reporter plasmid. pRL-tk-LUC was co-transfected as an internal control for transfection efficiency. Reportergene activity after sorafenib treatment (SORA) was measured using a Dual-Luciferase Reporter Assay as recently described [17]. Results are expressed in percent transactivation of dihydrotestosterone (DHT)-treated cells which were set at 100%; *p < 0.05; **p < 0.01; ***p < 0.001.
Mentions: Recently, sorafenib was shown to target AR-signalling in LNCaP and castration resistant LNCaP-sublines (LNCaP-abl, LNCaP-IL6+, LNCaP-Bic) [15]. As LNCaP cells express a promiscuous full length AR (919 amino acids, point mutation in the LBD, T877A) [16], we analyzed the effects of sorafenib on AR-signalling in PC-3 cells transiently transfected with a wild type AR. As seen in Figure 1, sorafenib diminished transactivation of AR-dependent reportergene constructs (ARE(2x), PSA) in PC-3 cells. Inhibition was already significant for the PSA-reporter at a concentration of 2.5 μM (downregulation versus DHT-treated controls: 23% ± 11%, p = 0.034), reaching its maximum at 10 μM, (downregulation versus DHT-treated controls: 60% ± 10%, p < 0.001; Figure 1A). Inhibition of ARE(2x)-promoter construct was relatively weak but statistically significant at concentrations >5μM (downregulation versus DHT-treated controls at 7.5 μM, 22% ± 6%, p = 0.033) reaching its maximum at 10 μM (downregulation 32% ± 4%, p = 0.002; Figure 1B). The reportergene assays are in agreement with previous findings, showing a sorafenib-induced downregulation of prostate specific antigen (PSA) in LNCaP and castration resistant LNCaP sublines [15].

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