Regulation of carcinogenesis and mediation through Wnt/β-catenin signaling by 3,3'-diindolylmethane in an enzalutamide-resistant prostate cancer cell line

Sci Rep. 2021 Jan 13;11(1):1239. doi: 10.1038/s41598-020-80519-3.


Enzalutamide (ENZ) is an important drug used to treat castration-resistant prostate cancer (CRPC), which inhibits androgen receptor (AR) signaling. Previous study showed that 3,3'-diindolylmethane (DIM) is an AR antagonist that also inhibits Wnt signaling and epithelial-mesenchymal transition (EMT). To investigate whether combined treatment with ENZ and DIM can overcome ENZ resistance by regulating Wnt signaling to inhibit AR signaling and EMT in ENZ-resistant prostate cancer cells, 22Rv1 cells were cultured in normal medium and treated with ENZ, DIM, and DIM with ENZ. Exposure of ENZ-resistant cells to both DIM and ENZ significantly inhibited cell proliferation without cytotoxicity and invasion in comparison with the control. DIM significantly increased the E-cadherin expression and inhibited the expressions of Vimentin and Fibronectin, subsequently inhibiting EMT. Co-treatment with ENZ and DIM significantly increased the expressions of GSK3β and APC and decreased the β-catenin protein expression, causing inhibition of Wnt signaling and AR expression, it also significantly decreased the AR-v7 expression and down-regulated AR signaling. Via suppression of Wnt and AR signaling, co-treatment increased the E-cadherin and decreased the Vimentin and Fibronectin RNA and protein expressions, then inhibited EMT. Co-treatment with DIM and ENZ regulated Wnt signaling to reduce not only the AR expression, but also the AR-v7 expression, indicating suppression of EMT that inhibits cancer cell proliferation, invasion and migration to ameliorate ENZ resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / pharmacology*
  • Carcinogenesis / drug effects*
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Indoles / pharmacology*
  • Male
  • Nitriles / pharmacology*
  • Phenylthiohydantoin / pharmacology*
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Wnt Signaling Pathway / drug effects*


  • Benzamides
  • Indoles
  • Nitriles
  • Phenylthiohydantoin
  • enzalutamide
  • 3,3'-diindolylmethane