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Down-regulation of Suppressor of Cytokine Signaling-3 Causes Prostate Cancer Cell Death through Activation of the Extrinsic and Intrinsic Apoptosis Pathways

¹ Department of Urology, Innsbruck Medical University, Innsbruck, Austria; ² Institute of Clinical Pathology, Medical University of Vienna; ³ Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; ⁴ Centocor Research and Development, Malvern, Pennsylvania; and ⁵ Department of Urology, General Hospital Feldkirch, Feldkirch, Austria

Requests for reprints: Zoran Culig, Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. Phone: 43-512-504-24717; Fax: 43-512-504-24817; Email: zoran.culig{at}i-med.ac.at.

Key Words: prostate cancer • suppressor of cytokine signaling • apoptosis • extrinsic and intrinsic pathways

Suppressor of cytokine signaling-3 (SOCS-3) acts as a negative feedback regulator of the Janus-activated kinase/signal transducers and activators of transcription factors signaling pathway and plays an important role in the development and progression of various cancers. To better understand the role of SOCS-3 in prostate cancer, SOCS-3 expression was down-regulated in DU-145, LNCaP-IL-6+, and PC3 cells by consecutive SOCS-3 small interfering RNA transfections. SOCS-3 mRNA and protein expression as measured by quantitative reverse transcription-PCR and Western blot, respectively, were decreased by 70% to 80% compared with controls. We observed a significant decrease in cell proliferation and viability in all SOCS-3–positive cell lines but not in the parental LNCaP cell line, which is SOCS-3 negative. In this study, we show that down-regulation of SOCS-3 leads to an increased cell death in prostate cancer cell lines. We found a considerable increase in the activation of the proapoptotic caspase-3/caspase-7, caspase-8, and caspase-9. A significant up-regulation of cleaved poly(ADP-ribose) polymerase and inhibition of Bcl-2 expression was observed in all SOCS-3–positive cell lines. Overexpression of Bcl-2 could rescue cells with decreased SOCS-3 levels from going into apoptosis. Tissue microarray data prove that SOCS-3 is highly expressed in castration-refractory tumor samples. In conclusion, we show that SOCS-3 is an important protein in the survival machinery in prostate cancer and is overexpressed in castration-resistant tumors. SOCS-3 knockdown results in an increase of cell death via activation of the extrinsic and intrinsic apoptosis pathways. [Cancer Res 2009;69(18):7375–84]