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

BACKGROUND. One of the mechanisms through which prostate cancers relapse du ring anti-androgen therapy may involve adaptation to low concentrations of androgen induced by anti-androgen therapies. Recent studies from our labora tory have reported that tumor necrosis factor-alpha (TNF alpha) is secreted from prostate cancer epithelial cells and LNCaP cells. We hypothesized tha t TNFa changes androgen-sensitivity in LNCaP cells. METHODS. We cultured LNCaP cells for more than 3 months in the presence of 50 ng/ml TNF alpha and established TNF alpha -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 promot er 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 cel ls. At 1 nM DHT, the anti-androgen bicalutamide stimulated LN-TR2 and inhib ited LNCaP proliferation. CONCLUSIONS. Long-term exposure of TNF alpha causes hypersensitivity to DHT in LNCaP and this was associated with increased nuclear AR protein. Furthe rmore, hypersensitivity to androgen caused anti-androgen withdrawal phenome non in the presence of DHT although bicalutamide itself did not stimulate L NCaP proliferation without androgen. This result may be one possible mechan ism for the anti-androgen withdrawal phenomenon. Prostate 46:319-326, 2001. (C) 2001 Wiley-Liss, Inc.