Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling

Abstract

Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells–macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion. Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway. Addition of CCR2 antagonist reversed the Casodex/MDV3100-induced macrophage migration and PCa cell invasion. In contrast, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation. These findings were confirmed in the in vivo mouse model with orthotopically injected TRAMP-C1 cells. Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.

Inhibition of Protein Kinase C/Twist1 Signaling Augments Anticancer Effects of Androgen Deprivation and Enzalutamide in Prostate Cancer

“…1C), PKC phosphorylation, and Twist1 protein expression, which was accompanied by a decreased E-cadherin and an increased fibronectin expression (Fig. 1D), consistently with the previous reports on EMT promotion by enzalutamide (27,28).…”

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

“…We thus conclude that SOCS3 is not directly regulated by the androgen receptor. Recent publications demonstrated that anti-androgen treatment can enhance STAT3 activity (15,46). Indeed, we could not only confirm an increased STAT3 activation after treatment with enzalutamide but also achieve complete reversal of the effect on SOCS3 by blocking the transcriptional activity of STAT3.…”

“…Activated STAT3 has been found in primary as well as in metastatic prostate cancer and correlates with Gleason score, tumor stage, and castration resistance (11,13). Constitutively active STAT3 has been shown to confer enzalutamide resistance (14), and STAT3 has been implicated in promoting metastasis during treatment with the antiandrogens bicalutamide and enzalutamide (15). Furthermore, STAT3 has been shown to bind and trans-activate the N-terminal domain of the AR (7), which may lead to enhanced activation of the androgen receptor and drive progression to castration resistance.…”

Androgen receptor antagonists for prostate cancer therapy

“…They all inhibit PCa proliferation and reduce PSA levels, but only ASC-J9 was able to suppress cell invasion and thus the formation of metastases in in vitro and in vivo models (Lin et al 2013a). A different modulation of the STAT3-CCL2 signaling pathway was suggested to lie at the base of this observed difference (Lin et al 2013b).…”