Down-regulation of suppressor of cytokine signaling-3 causes prostate cancer cell death through activation of the intrinsic apoptosis pathway

Suppressor of cytokine signaling (SOCS) -3 acts as a negative feedback regulator of the Janus kinase/signal transducers and activators of transcription factors signaling pathway and plays an important role in the development and progression of various cancers. In order 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 siRNA transfections. SOCS-3 mRNA and
protein expression as measured by qRT-PCR and Western blot, respectively, were decreased approximately 70-80 % compared to 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 remarkable increase in the activation of the pro-apoptotic caspases 3 and 9. A significant up-regulation of cPARP 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 knock down results in an increase in cell death via activation of the intrinsic apoptosis pathway.