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

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.

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

“…For example, in a study by Izumi et al, the silencing of AR in LNCaP cells and PCa mouse xenograft models was shown to promote cell migration by up-regulating the CCL2-dependent STAT3 and EMT pathways. The authors suggest that co-targeting CCL2/CCR2-STAT3 signaling may provide a novel therapeutic approach for targeting PCa progression and metastasis at the castration-resistant stage (Izumi et al 2013). In another study, ADT induced cell invasion that was reversed by targeting pSTAT3-CCL2 signaling in PCa cells and in mouse models .…”

“…Multiple studies have shown that mesenchymal markers, including N-cadherin, vimentin, ZEB1, TWIST, and SNAI2, are highly expressed in androgen-deprived patient tumors, cell lines, and xenografts and mouse models, and a number of AR-dependent mechanisms of EMT control have been proposed (Liu et al 2008, Sun et al 2012, Izumi et al 2013. In patientderived tissue slice grafts, 6-10 weeks of flutamide or lupron treatment was shown to induce the expression of the mesenchymal marker vimentin and to cause the mislocalization of E-cadherin (Zhao et al 2013).…”

Inflammation and prostate cancer: friends or foe?

“…As an example, the more aggressive types of prostate cancer cell lines express higher levels of CCR2 compared with less aggressive cells and both CCR2 mRNA and protein levels increase in metastatic prostate cancers compared with localized ones [101]. So far, the signals and the mechanism of regulating the chemokine system in prostate cancer remain poorly studied and recently, most studies have analyzed the effects of nuclear receptors such as androgen [102,103] and vitamin D3 receptors [104].…”

Androgen receptor as a regulator of ZEB2 expression and its implications in epithelial-to-mesenchymal transition in prostate cancer

“…While some investigators have reported androgen-induced activation of EMT and its effectors (Zhu & Kyprianou 2010, Anose & Sanders 2011, others have demonstrated EMT activation in response to androgen deprivation (Sun et al 2012). A recent study by Izumi et al (2013) has implicated AR as an inhibitor of EMT activation in PCa cells. These conflicting data warrant more studies directed toward deciphering the role of androgenic stimuli in EMT and PCa metastasis.…”