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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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Related in: MedlinePlus

Downmodulation of AR and AR-V in 22Rv1 cells is due to sorafenib induced proteasomal degradation. 22Rv1 cells were incubated with the proteasome inhibitor MG132 (5 μM) for 60 min followed by treatment with sorafenib (5 μM) for 18 h. Subsequently cell extracts were analyzed by Western blot analysis (AR: androgen receptor; AR-V, ARΔLBD generated by alternative splicing; β-actin: loading control; ctrl: untreated control; SORA: sorafenib; MG132: proteasome inhibitor). AR, AR-V and β-actin levels were quantified by densitometry and expressed as fold-change of AR/β-actin or AR-V/β-actin control (ctrl) levels which were set at 1.00.
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f3-ijms-13-11530: Downmodulation of AR and AR-V in 22Rv1 cells is due to sorafenib induced proteasomal degradation. 22Rv1 cells were incubated with the proteasome inhibitor MG132 (5 μM) for 60 min followed by treatment with sorafenib (5 μM) for 18 h. Subsequently cell extracts were analyzed by Western blot analysis (AR: androgen receptor; AR-V, ARΔLBD generated by alternative splicing; β-actin: loading control; ctrl: untreated control; SORA: sorafenib; MG132: proteasome inhibitor). AR, AR-V and β-actin levels were quantified by densitometry and expressed as fold-change of AR/β-actin or AR-V/β-actin control (ctrl) levels which were set at 1.00.

Mentions: Interestingly, sorafenib was able to diminish both full length AR as well as AR-V in 22Rv1 cells. Downregulation of AR and AR-V protein levels following sorafenib treatment could be rescued by the proteasome inhibitor MG132, the latter suggesting that sorafenib induces a proteasomal degradation of AR- and ARΔLBD molecules in PCa cells (Figure 3).


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)

Downmodulation of AR and AR-V in 22Rv1 cells is due to sorafenib induced proteasomal degradation. 22Rv1 cells were incubated with the proteasome inhibitor MG132 (5 μM) for 60 min followed by treatment with sorafenib (5 μM) for 18 h. Subsequently cell extracts were analyzed by Western blot analysis (AR: androgen receptor; AR-V, ARΔLBD generated by alternative splicing; β-actin: loading control; ctrl: untreated control; SORA: sorafenib; MG132: proteasome inhibitor). AR, AR-V and β-actin levels were quantified by densitometry and expressed as fold-change of AR/β-actin or AR-V/β-actin control (ctrl) levels which were set at 1.00.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3-ijms-13-11530: Downmodulation of AR and AR-V in 22Rv1 cells is due to sorafenib induced proteasomal degradation. 22Rv1 cells were incubated with the proteasome inhibitor MG132 (5 μM) for 60 min followed by treatment with sorafenib (5 μM) for 18 h. Subsequently cell extracts were analyzed by Western blot analysis (AR: androgen receptor; AR-V, ARΔLBD generated by alternative splicing; β-actin: loading control; ctrl: untreated control; SORA: sorafenib; MG132: proteasome inhibitor). AR, AR-V and β-actin levels were quantified by densitometry and expressed as fold-change of AR/β-actin or AR-V/β-actin control (ctrl) levels which were set at 1.00.
Mentions: Interestingly, sorafenib was able to diminish both full length AR as well as AR-V in 22Rv1 cells. Downregulation of AR and AR-V protein levels following sorafenib treatment could be rescued by the proteasome inhibitor MG132, the latter suggesting that sorafenib induces a proteasomal degradation of AR- and ARΔLBD molecules in PCa cells (Figure 3).

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