ASC-J9(®), and not Casodex or Enzalutamide, suppresses prostate cancer stem/progenitor cell invasion via altering the EZH2-STAT3 signals

Cancer Lett. 2016 Jul 1;376(2):377-86. doi: 10.1016/j.canlet.2016.01.057. Epub 2016 Apr 1.

Abstract

Early studies suggested that prostate cancer (PCa) stem/progenitor (S/P) cells might play key roles to promote the tumor initiation and metastasis. Yet their linkage to the failure of androgen deprivation therapy (ADT), however, remains unclear. Here we demonstrated that the ADT with anti-androgens Casodex (also known as Bicalutamide) and Enzalutamide (also known as MDV3100), but not the newly identified AR degradation enhancer, ASC-J9(®), increased PCa S/P population, which might then lead to enhance the PCa cell invasion. Targeting AR with ASC-J9(®), and not targeting androgens with Casodex or Enzalutamide, led to suppress PCa S/P cell invasion. Mechanism dissection revealed ASC-J9(®) could suppress S/P cell invasion via altering the EZH2/STAT3 and/or AKT/EZH2/STAT3 signals. Together, these results suggest that targeting PCa S/P cells with ASC-J9(®) or inhibitors to interrupt the EZH2/STAT3 and/or Akt/EZH2/STAT3 signals may become a new therapy to overcome the unwanted side effects of Casodex or Enzalutamide to further suppress the PCa metastasis.

Keywords: ASC-J9(®); Androgen deprivation therapy; EZH2; Prostate cancer; Stem/progenitor cell.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology*
  • Anilides / pharmacology*
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Benzamides
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Curcumin / analogs & derivatives*
  • Curcumin / pharmacology
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Humans
  • Male
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Nitriles / pharmacology*
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / pharmacology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Side-Population Cells / drug effects
  • Side-Population Cells / metabolism
  • Side-Population Cells / pathology
  • Signal Transduction / drug effects*
  • Tosyl Compounds / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one
  • Androgen Antagonists
  • Anilides
  • Antineoplastic Agents, Hormonal
  • Benzamides
  • Nitriles
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tosyl Compounds
  • Phenylthiohydantoin
  • enzalutamide
  • bicalutamide
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Proto-Oncogene Proteins c-akt
  • Curcumin