Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells.

Signal transducers and activators of transcription (STATs) were identified originally as key components of cytokine signaling pathways. More recently, constitutive activation of STAT proteins has been detected in a wide variety of human tumor specimens and tumor cell lines. Here, we examined the activation of one STAT family member, Stat3, in human prostate cancer cell lines and primary prostate tumors. An analysis of 45 adenocarcinomas obtained at radical prostatectomy revealed elevated levels of constitutive Stat3 activation in 37 (82%) of 45 of the tumors compared with matched adjacent nontumor prostate tissues. A highly specific immunohistochemical assay for detection of phospho-Stat3 revealed that elevated Stat3 activity was localized primarily in the tumor cells of prostate carcinoma specimens. Furthermore, higher levels of Stat3 activation in patient specimens were correlated significantly with more malignant tumors exhibiting higher Gleason scores. In addition, all of the three human prostate cancer cell lines examined (DU145, PC3, and LNCaP) displayed constitutive activation of Stat3. Substantially lower levels of Stat3 activation were detected in LNCaP cells; however, stimulation with interleukin 6 induced a significant increase in Stat3 DNA-binding activity in these cells. Moreover, the direct inhibition of constitutive Stat3 signaling in DU145 cells using antisense Stat3 oligonucleotides induced growth inhibition and apoptosis. Our findings demonstrate that constitutive activation of Stat3 occurs frequently in primary prostate adenocarcinomas and is critical for the growth and survival of prostate cancer cells. These studies further suggest that Stat3 signaling represents a potentially novel molecular target for prostate cancer therapy.