STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells

BACKGROUND. In the human prostate cancer cell line LNCaP, interleukin (IL)- 6 has been shown to regulate both growth and neuroendocrine (NE) differenti ation.. We recently observed that IL-6 mediated growth arrest in LNCaP by a ctivating STAT 3. Since differentiation and growth arrest are often associa ted processes, we investigated whether STATE also mediated NE differentiati on in this prostate cancer cell line. METHODS. We treated previously characterized clones LNCaP-neo (neomycin-res istant LNCaP) and LNCaP-SF (LNCaP-STAT3 dominant negative mutant) with IL-6 and screened for NE differentiation by observing morphological changes and immunoblotting for two NE markers, neuron-specific enolase (NSE) and chrom ogranin A (ChA). To characterize further the role of STATE in growth arrest and differentiation, we transfected a wild-type STAT3 vector into PC-3 cel ls and generated a subclone PC-3-S3. In this clone, we assessed differentia tion by observing morphological changes and determined growth responses by cell counting and clonogenic assays. RESULTS. We observed that IL-6 induced formation of neurite extensions, mor phologic features associated with NE differentiation, and enhanced expressi on of neuronal markers ChA and NSE in LNCaP-neo cells. In contrast, LNCaP-S F, possessing a dominant negative mutant form of STATE, exhibited no charac teristics of IL-6 induced NE differentiation. Furthermore, expression of a constitutively phosphorylated wild-type STATE in PC-3 cells inhibited growt h and induced the formation of neurite extensions and NSE expression. CONCLUSIONS. These results indicate that STATE is a mediator of both NE dif ferentiation and growth inhibition in LNCaP and PC-3, suggesting a connecti on between growth inhibition and NE differentiation in prostate cancer.