Abstract
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.
Highlights
Prostate cancer (PCa) is the most common malignancy and the third leading cause of cancer death in males in the United States and many other countries (Siegel et al, 2011)
CCL2 is responsible for increased cell migration after targeting androgen receptor (AR) with siRNA in prostate cancer (PCa) and macrophages To investigate the role of AR and mimic the crosstalk between macrophages and PCa cells in the tumour microenvironment, we established an in vitro co‐culture model that allows the crosstalk between infiltrating macrophages and PCa cells in the presence or absence of AR silencing
We determined whether silencing macrophage AR function via lentiviral AR‐siRNA using scramble RNA as a control, would modulate behaviours of PCa cells during co‐culture since we hypothesized that infiltrating macrophages could be increased during androgen deprivation therapy (ADT) and the macrophage function could possibly be affected by targeting AR with siAR
Summary
Prostate cancer (PCa) is the most common malignancy and the third leading cause of cancer death in males in the United States and many other countries (Siegel et al, 2011). Our previous study on molecular pathways linking AR function in macrophages and wound healing‐ associated inflammation showing that the deficit of AR in mice tends to create an immunosuppressive microenvironment that favours wound healing (Lai et al, 2009). These studies found a potential role for AR in mediating inflammatory responses during PCa progression since gene signatures of wound healing responses are very similar to genes identified in studies of progressive breast cancer with high metastatic potential (Chang et al, 2005). This study highlights the important roles of CCL2 in directing infiltrating macrophages to enhance PCa progression/metastasis
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