Enhanced androgen receptor signaling correlates with the androgen-refractory growth in a newly established MDA PCa 2b-hr human prostate cancer cell subline

Cancer Res. 2003 Sep 1;63(17):5622-8.

Abstract

Bone metastasis is commonly found in prostate cancer (PC) patients. Although the mechanisms for the recurrence of bone metastasis-derived PC during medical or surgical castration therapy are still unclear because of the lack of suitable experimental models, one hypothesis is that enhanced androgen receptor (AR) signaling causes androgen-refractory PC growth. To test this hypothesis, we first established a novel androgen-refractory MDA PCa 2b cell subline, MDA PCa 2b-hr, which was generated in vitro from bone metastasis-derived, androgen-dependent MDA PCa 2b human PC cells after approximately 35 weeks of growth suppression by androgen-depletion treatment to mimic the clinical PC recurrence during androgen-ablation therapy. The changes of the androgen responsiveness of growth and the AR expression levels during the transition from an androgen-dependent to androgen-refractory proliferative phase through a temporal growth-suppressed phase precisely paralleled that of the basal growth rate. Furthermore, the androgen-refractory growth of MDA PCa 2b-hr cells in androgen-depleted medium was suppressed by an antiandrogen, bicalutamide. Next, we established nude mouse xenograft models to clarify whether AR signaling in MDA PCa 2b-hr cells is also enhanced in vivo. Both the MDA PCa 2b and MDA PCa 2b-hr tumors grew in gonadally intact mice, but only the MDA PCa 2b-hr tumors grew in castrated mice. The growth rate of MDA PCa 2b-hr tumors was significantly higher in gonadally intact mice than in castrated mice. Treatment with dehydroepiandrosterone pellets, which produced clinical castration levels of serum testosterone, accelerated the MDA PCa 2b-hr but not MDA PCa 2b tumor growth in castrated mice and increased blood prostate-specific antigen levels in castrated mice bearing MDA PCa 2b-hr tumors but not in mice bearing MDA PCa 2b tumors. Our data suggest that the enhanced AR signaling should be closely correlated with the androgen-refractory growth of human bone metastasis-derived PC, which might come to use adrenal androgens remaining in the blood even after castration therapy and warrant the continuation of hormone therapy for the recurrent PC.

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgens / deficiency
  • Androgens / physiology*
  • Anilides / pharmacology
  • Animals
  • Cell Division / drug effects
  • Cell Division / physiology
  • Dehydroepiandrosterone / pharmacology
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms, Hormone-Dependent / pathology*
  • Nitriles
  • Orchiectomy
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Receptors, Androgen / biosynthesis
  • Receptors, Androgen / physiology*
  • Signal Transduction / physiology
  • Tosyl Compounds
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Androgen Antagonists
  • Androgens
  • Anilides
  • Nitriles
  • Receptors, Androgen
  • Tosyl Compounds
  • Dehydroepiandrosterone
  • bicalutamide