Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling.

Abstract

Androgen receptor (AR) signaling is important for prostate cancer progression. However, androgen-deprivation and/or AR targeting-based therapies often lead to resistance. Here, we demonstrate that loss of AR expression results in STAT3 activation in prostate cancer cells. AR downregulation further leads to development of prostate cancer stem-like cells (CSC), which requires STAT3. In human prostate tumor tissues, elevated cancer stem-like cell markers coincide with those cells exhibiting high STAT3 activity and low AR expression. AR downregulation-induced STAT3 activation is mediated through increased interleukin (IL)-6 expression. Treating mice with soluble IL-6 receptor fusion protein or silencing STAT3 in tumor cells significantly reduced prostate tumor growth and CSCs. Together, these findings indicate an opposing role of AR and STAT3 in prostate CSC development.

• Authors: Anne Schroeder, Andreas Herrmann, Gregory Cherryholmes, Claudia Kowolik, Ralf Buettner, Sumanta Pal, Hua Yu, Gerhard Müller-Newen, Richard Jove
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 4 Pg. 1227-37 (Feb 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24177177 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Receptors, Androgen
• STAT3 Transcription Factor

Topics

• Adenocarcinoma (genetics, pathology)
• Animals
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Neoplastic Stem Cells (metabolism, pathology)
• Phenotype
• Prostatic Neoplasms (genetics, pathology)
• RNA Interference (physiology)
• Receptors, Androgen (genetics)
• STAT3 Transcription Factor (physiology)
• Signal Transduction (genetics)
• Tumor Cells, Cultured