D, L-Sulforaphane (SFN), a synthetic analogue of broccoli-derived L-isomer, inhibits viability of human prostate cancer cells in culture and in vivo. We also showed recently that oral administration of SFN prevents development of prostate cancer and pulmonary metastasis in a transgenic mouse model (TRAMP mice) by reducing cell proliferation and augmenting activity of natural killer cells. However, the mechanism underlying anticancer effect of SFN is not fully understood. We now demonstrate that SFN inhibits constitutive and interleukin 6 (IL6)-induced activation of signal transducer and activator of transcription 3 (STAT3), which is implicated in development and progression of prostate cancer. Growth suppressive concentrations of SFN (20 and 40 μmol/L) inhibited constitutive (DU145 cells) and IL6-induced (LNCaP cells) phosphorylation of STAT3 (Tyr705) as well as its upstream regulator Janus-activated kinase 2 (JAK2; Tyr1007/1008). Treatment of DU145 and LNCaP cells with SFN resulted in suppression of IL6-induced transcriptional activity of STAT3 as revealed by luciferase reporter assay and nuclear translocation of STAT3 as judged by immunofluorescence microscopy. The SFN-mediated inhibition of STAT3 activation was due to down-regulation of JAK2 mRNA expression in both cell lines. Levels of many STAT3-regulated gene products including Bcl-2, cyclin D1, and survivin were also down-regulated in SFN-treated cells. The IL6-mediated activation of STAT3 conferred partial but marked protection against SFN-induced apoptosis in LNCaP cells as evidenced by cleavage of poly-(ADP-ribose)-polymerase and caspase-3 and cytoplasmic histone-associated DNA fragmentation. In addition, siRNA knockdown of STAT3 in DU145 cells resulted in a modest yet statistically significant increase in SFN-induced apoptotic DNA fragmentation. The results of the present study demonstrate SFN-mediated inhibition of STAT3 activation in human prostate cancer cells. This investigation was supported by the National Cancer Institute grant CA115498-05.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3787.