237 The multikinase inhibitor sorafenib suppresses AR expression and signaling and induces apoptosis of castration therapy-resistant prostate cancer cells

237 - The multikinase inhibitor sorafenib suppresses AR expression and signaling and ind... Page 1 of 1

e237 The multikinase inhibitor sorafenib suppresses AR expression and signaling and induces apoptosis of castration therapy-resistant prostate cancer cells Oh S.J.1, Erb H.1, Hobisch A.2, Santer F.R.1, Culig Z.1 1Innsbruck

Medical University, Dept. of Urology, Innsbruck, Austria, 2General Hospital Feldkirch, Dept. of Urology, Feldkirch, Austria INTRODUCTION & OBJECTIVES: Standard therapy of non-organ-confined prostate cancer aims to inhibit androgen receptor (AR) signaling. The effectivity of these therapies is limited and the development of alternative approaches is in need. In the present study, we report on the use of the multikinase inhibitor sorafenib in prostate cancer parental cells and derivatives which mimic endocrine therapy-resistant prostate cancers. MATERIAL & METHODS: We used LNCaP cells and the therapy-resistant sublines LNCaPBic and LNCaP-Abl obtained by prolonged treatment with bicalutamide and long-term androgen ablation, respectively. The treatment was performed in serum-free hormonesupplemented HITES medium with physiologic concentrations of sorafenib (0-4µM) for 48 h. Apoptosis was measured by caspase 3/7 assays and flow cytometry with annexin V staining. Expression of AR and apoptosis regulatory proteins was determined using Western blot. AR mRNA levels were measured by RT-PCR and secreted PSA was measured by an immunoassay. Proliferation was evaluated by 3H-thymidine incorporation assay. RESULTS: LNCaP-Abl and LNCaP Bic showed increased AR and Mcl-1 expression compared to parental cells. The treatment with sorafenib resulted in downregulation of Mcl-1 and dephosphorylation of AKT thus stimulating apoptosis of prostate cancer cells. Although concentrations of sorafenib required for apoptosis induction in therapy-resistant sublines were higher than those needed in parental LNCaP cells, the drug showed efficacy in cells which became resistant to bicalutamide and chronic androgen deprivation. Interestingly, sorafenib showed an inhibitory effect on AR mRNA and protein expression in all cell lines. In LNCaP and LNCaP-Bic cells, secreted PSA levels were dramatically reduced in presence of sorafenib. This inhibition was stronger than that caused by bicalutamide. In cells in which AR expression was down-regulated by siRNA, the treatment with sorafenib increased apoptosis in an additive manner. No significant difference between parental and resistant cells was observed with regard to the extent of growth inhibition. CONCLUSIONS: Sorafenib causes an inhibitory effect on androgen signaling through downregulation of AR mRNA and protein and stimulates apoptosis of hormone therapyresistant prostate cancer cells with AR overexpression. Furthermore, efficacy of sorafenib may be enhanced in combination with other agents which downregulate AR. These results suggest that sorafenib treatment could be considered as an adjuvant option in combination with androgen ablation and could also have beneficial effects in prostate cancer progression.

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4/6/2012