Long-term exposure of tumor necrosis factor alpha causes hypersensitivity to androgen and anti-androgen withdrawal phenomenon in LNCaP prostate cancer cells

Prostate. 2001 Mar 1;46(4):319-26. doi: 10.1002/1097-0045(20010301)46:4<319::aid-pros1039>3.0.co;2-c.


Background: One of the mechanisms through which prostate cancers relapse during anti-androgen therapy may involve adaptation to low concentrations of androgen induced by anti-androgen therapies. Recent studies from our laboratory have reported that tumor necrosis factor-alpha (TNFalpha) is secreted from prostate cancer epithelial cells and LNCaP cells. We hypothesized that TNFalpha changes androgen-sensitivity in LNCaP cells.

Methods: We cultured LNCaP cells for more than 3 months in the presence of 50 ng/ml TNFalpha and established TNFalpha-resistant LNCaP cells (LN-TR2). Sensitivity to androgen was examined by the cell proliferation assay. We also transfected LNCaP and LN-TR2 cells with a luciferase reporter plasmid driven by prostate-specific antigen (PSA) promoter and compared PSA promoter activity. Nuclear localization of AR protein that binds to target genes was also examined by Western blotting.

Results: LN-TR2 cells had increased sensitivity to dihydrotestosterone (DHT) (i.e., proliferation and PSA promoter activation) than LNCaP cells. Total AR mRNA and AR protein levels were decreased in LN-TR2 cells. However, LN-TR2 cells demonstrated increased levels of nuclear AR compared to LNCaP cells. At 1 nM DHT, the anti-androgen bicalutamide stimulated LN-TR2 and inhibited LNCaP proliferation.

Conclusions: Long-term exposure of TNFalpha causes hypersensitivity to DHT in LNCaP and this was associated with increased nuclear AR protein. Furthermore, hypersensitivity to androgen caused anti-androgen withdrawal phenomenon in the presence of DHT although bicalutamide itself did not stimulate LNCaP proliferation without androgen. This result may be one possible mechanism for the anti-androgen withdrawal phenomenon.

MeSH terms

  • Androgen Antagonists / pharmacology*
  • Anilides / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Blotting, Northern
  • Blotting, Western
  • Dihydrotestosterone / metabolism*
  • Humans
  • Luciferases / analysis
  • Male
  • Nitriles
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism*
  • Time Factors
  • Tosyl Compounds
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism*


  • Androgen Antagonists
  • Anilides
  • Antineoplastic Agents
  • Nitriles
  • Tosyl Compounds
  • Tumor Necrosis Factor-alpha
  • Dihydrotestosterone
  • bicalutamide
  • Luciferases