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

Despite androgen deprivation therapy (ADT) suppression of cancer of the prostate (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 presently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently brought to enhanced PCa cell invasion. In comparison, the AR degradation enhancer, ASC-J9, covered up both macrophage migration and subsequent PCa cell invasion. Mechanism dissection demonstrated that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression that has been enhanced the pSTAT3-CCL2 path. Inclusion of CCR2 antagonist reversed the Casodex/MDV3100-caused macrophage migration and PCa cell invasion. In comparison, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent path via inhibiting PIAS3 expression as well as an AR-independent path via direct inhibition from the STAT3 phosphorylation/activation. These bits of information were confirmed within the in vivo mouse model with Curcumin analog C1 orthotopically injected TRAMP-C1 cells. Together, these results may enhance the potential worry about the presently used ADT with anti-androgens that promotes PCa metastasis and could provide some better and new therapeutic strategies using ASC-J9 alone or perhaps a combinational therapy that concurrently targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to higher fight PCa growth and metastasis at castration-resistant stage.