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) differentiation. We recently observed that IL-6 mediated growth arrest in LNCaP by activating STAT 3. Since differentiation and growth arrest are often associated processes, we investigated whether STAT3 also mediated NE differentiation in this prostate cancer cell line.


METHODS
We treated previously characterized clones LNCaP-neo (neomycin-resistant 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 chromogranin A (ChA). To characterize further the role of STAT3 in growth arrest and differentiation, we transfected a wild-type STAT3 vector into PC-3 cells and generated a subclone PC-3-S3. In this clone, we assessed differentiation 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, morphologic features associated with NE differentiation, and enhanced expression of neuronal markers ChA and NSE in LNCaP-neo cells. In contrast, LNCaP-SF, possessing a dominant negative mutant form of STAT3, exhibited no characteristics of IL-6 induced NE differentiation. Furthermore, expression of a constitutively phosphorylated wild-type STAT3 in PC-3 cells inhibited growth and induced the formation of neurite extensions and NSE expression.


CONCLUSIONS
These results indicate that STAT3 is a mediator of both NE differentiation and growth inhibition in LNCaP and PC-3, suggesting a connection between growth inhibition and NE differentiation in prostate cancer.
Spiotto
M T
MT
Department of Radiation and Cellular Oncology and Division of Biological Sciences, Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Chung
T D
TD
D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators