Since differentiation and growth arrest are often associated processes, we investigated whether STAT3 also mediated NE differentiation in this prostate cancer cell line.
IL-6 signals through Janus kinase, signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinase and is also able to induce androgen receptor (AR)-mediated gene activation in prostate cancer, which is an important process in prostate cancer androgen-independent progression.
Our results demonstrate that expression of wt p53 but not mutant p53 significantly reduced tyrosine phosphorylation of Stat3 and inhibited Stat3 DNA binding activity in both DU145 and Tsu prostate cancer cell lines that express constitutively active Stat3.
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.
Screening of the prostate cancer cell lines LNCaP, PC3 and DU145 allowed the mapping of specific regions where genome copy number appeared altered and led to the identification of two novel regions of complete loss at 17q21.31 (500 kb spanning STAT3) and at 10q23.1 (50-350 kb spanning SFTPA2) in the PC3 cell line.
These results demonstrate that targeting Stat3 signaling using siRNA technique may serve as a novel therapeutic strategy for treatment of prostate cancer expressing constitutively activated Stat3.
Because we are interested in how persistently-activated STAT3 changes the cellular phenotype to a malignant one in prostate cancer, we used expression vectors containing a gene for constitutively-activated STAT3, called S3c, into NRP-152 rat and BPH-1 human benign prostatic epithelial cells.
Paraffin-embedded specimens from 92 patients with clinically localized prostate cancer who underwent radical prostatectomy without neoadjuvant treatment were analyzed by immunohistochemistry using two antibodies: anti-phospho-specific STAT3 (p-STAT3) antibody, which recognized only activated STAT3, and anti-total STAT3 antibody, which recognized both activated and inactivated STAT3.
These data indicate that Stat3 signaling is a promising molecular target for prostate cancer therapy and that vector-based Stat3 siRNA may be useful as a therapeutic agent for treatment of prostate cancer.
Moreover, in malignant cells harboring constitutively-active Stat3, including human prostate cancer DU145 cells and v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), resveratrol treatment represses Stat3-regulated cyclin D1 as well as Bcl-xL and Mcl-1 genes, suggesting that the antitumor cell activity of resveratrol is in part due to the blockade of Stat3-mediated dysregulation of growth and survival pathways.
The interaction of PKCepsilon with Stat3 was observed in human prostate cancer, human prostate cancer cell lines (LNCaP, DU145, PC3, and CW22rv1), and prostate cancer that developed in transgenic adenocarcinoma of mouse prostate mice.
The coding sequences for GRIM-19, a cellular STAT3-specific inhibitor, and Stat3-specific shRNAs were used to create a dual expression plasmid vector and used for prostate cancer therapy in vitro and in mouse xenograft models in vivo.
The effects of Stat5a/b on the viability of prostate cancer cells involve Stat5a/b regulation of Bcl-X(L) and cyclin D1 protein levels but not the expression or activation of Stat3.
Previously, we reported that single-stranded oligonucleotides containing consensus STAT3 binding sequences (13410 and 13411) were more effective for inducing apoptosis in prostate cancer cells than antisense STAT3 oligonucleotides.
The interaction between STAT3 and Fer was observed in all prostate cancer cell lines tested, and this interaction is mediated via the Fer Src homology 2 domain and modulated by interleukin-6 (IL-6).
Cell proliferation, cell cycle, Western blot, gene transfer, and reporter assays were used to test the effects of PEITC on the growth and IL6/JAK/STAT3 pathway in prostate cancer.