Details

Autor(en) / Beteiligte

• Izumi, Kouji
• Fang, Lei‐Ya
• Mizokami, Atsushi
• Namiki, Mikio
• Li, Lei
• Lin, Wen‐Jye
• Chang, Chawnshang

Titel

Targeting the androgen receptor with siRNA promotes prostate cancer metastasis through enhanced macrophage recruitment via CCL2/CCR2‐induced STAT3 activation

Ist Teil von

• EMBO molecular medicine, 2013-09, Vol.5 (9), p.1383-1401

Ort / Verlag

England: EMBO Press

Erscheinungsjahr

2013

Link zum Volltext

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• Increased CCL2 expression in prostate cancer (PCa) cells enhanced metastasis via macrophage recruitment. However, its linkage to androgen receptor (AR)‐mediated PCa progression remains unclear. Here, we identified a previously unrecognized regulation: targeting AR with siRNA in PCa cells increased macrophage recruitment via CCL2 up‐regulation, which might then result in enhancing PCa invasiveness. Molecular mechanism dissection revealed that targeting PCa AR with siRNA promoted PCa cell migration/invasion via CCL2‐dependent STAT3 activation and epithelial–mesenchymal transition (EMT) pathways. Importantly, pharmacologic interruption of the CCL2/CCR2‐STAT3 axis suppressed EMT and PCa cell migration, providing a new mechanism linking CCL2 and EMT. Simultaneously targeting PCa AR with siRNA and the CCL2/CCR2‐STAT3 axis resulted in better suppression of PCa growth and metastasis in a xenograft PCa mouse model. Human PCa tissue microarray analysis suggests that increased CCL2 expression may be potentially associated with poor prognosis of PCa patients. Together, these results may provide a novel therapeutic approach to better battle PCa progression and metastasis at the castration resistant stage via the combination of targeting AR with siRNA and anti‐CCL2/CCR2‐STAT3 signalling. Ablation of androgen receptor in myeloid or prostate cells promotes metastatic progression of prostate cancer cells through induction of CCL2 via STAT3 activation by down‐regulation of the STAT3 inhibitor PIAS3.