Abstract 838: Suppression of constitutive and interleukin-6-inducible activation of signal transducer and activator of transcription 3 in human prostate cancer cells by diallyl trisulfide, a cancer chemopreventive constituent of garlic

Abstract

Abstract Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor implicated in prostate cancer development. The STAT3 is constitutively active in a large fraction of human prostate cancer cells and clinical prostate cancer specimens. Hyperactivity of STAT3 is associated with advanced prostate cancer. Furthermore, STAT3 activation promotes survival and inhibits apoptosis in prostate cancer cells. Agents that are safe but can either suppress activation of STAT3 or overcome STAT3 activation for their anticancer effects are attractive for prevention and treatment of prostate cancer. Natural products have attracted tremendous attention for the discovery of novel agents potentially useful for prevention and treatment of human cancers. The present study demonstrates that diallyl trisulfide (DATS), a promising cancer chemopreventive constituent of processed garlic, inhibits phosphorylation (activation) of STAT3 in prostate cancer cells in culture and in vivo. Exposure of DU145 and LNCaP human prostate cancer cells to growth suppressive and pharmacologically-relevant concentrations of DATS (20 and 40 μmol/L) resulted in suppression of constitutive (DU145) as well as interleukin-6 (IL-6)-induced (LNCaP) phosphorylation of STAT3 (Tyr705). The DATS-mediated suppression of STAT3 activation correlated with inhibition of Janus-activated kinase 2 phosphorylation. Constitutive and/or IL-6-induced nuclear translocation of pSTAT3 as well as STAT3 dimerization was also inhibited markedly on treatment with DATS in both cell lines. Inhibition of prostate cancer development in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice by gavage with DATS correlated with a visible decrease in the levels of pSTAT3. Interestingly, the IL-6-mediated activation of STAT3 failed to confer protection against proapoptotic response to DATS in either cell line. Likewise, the DATS-mediated inhibition of cell migration was either not affected or minimally reversed by the IL-6 treatment or ectopic expression of constitutively active STAT3. In conclusion, the present study indicates that DATS treatment suppresses STAT3 phosphorylation in prostate cancer cells in culture and in vivo, but activation of this oncogenic transcription factor is largely dispensable for cellular responses to DATS. Ability of DATS to overcome STAT3 activation is a therapeutic advantage for this chemopreventive agent. This study was supported by the USPHS grant 2 RO1 CA113363-06, awarded by the National Cancer Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 838. doi:10.1158/1538-7445.AM2011-838