Diallyl Trisulfide Inhibits Activation of Signal Transducer and Activator of Transcription 3 in Prostate Cancer Cells In Culture and In Vivo

摘要

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor implicated in prostate carcinogenesis. The present study demonstrates that diallyl trisulfide (DATS), a promising cancer chemopreventive constituent of processed garlic, inhibits phosphorylation 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), which correlated with inhibition of Janus-activated kinase 2 phosphorylation. Constitutive and/or IL-6-induced nuclear translocation of pSTAT3 and 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 of DATS correlated with a visible decrease in the levels of pSTAT3. Interestingly, the IL-6-mediated activation of STAT3 largely failed to confer protection against proapoptotic response to DATS in both cells. 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.