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 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.
George Whipple Lab for Cancer Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
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D000726:Androgen Antagonists / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002465:Cell Movement / Q000187:drug effects; D054405:Chemokine CCL3 / Q000378:metabolism / Q000502:physiology*; D018920:Coculture Techniques; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology*; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014105:Tosyl Compounds / Q000494:pharmacology*
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; D054405:Chemokine CCL3; D003474:Curcumin; D009570:Nitriles; D010669:Phenylthiohydantoin; D050796:STAT3 Transcription Factor; D014105:Tosyl Compounds; C471106:ASC-J9 compound; C515429:CCL3 protein, human; C540278:enzalutamide; C053541:bicalutamide