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Long‐term exposure of tumor necrosis factor α causes hypersensitivity to androgen and anti‐androgen withdrawal phenomenon in LNCaP prostate cancer cells
Author(s) -
Harada Shuji,
Keller Evan T.,
Fujimoto Naohiro,
Koshida Kiyoshi,
Namiki Mikio,
Matsumoto Tetsuro,
Mizokami Atsushi
Publication year - 2001
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/1097-0045(20010301)46:4<319::aid-pros1039>3.0.co;2-c
Subject(s) - lncap , bicalutamide , dihydrotestosterone , androgen , prostate cancer , endocrinology , medicine , cancer research , androgen receptor , tumor necrosis factor alpha , biology , cancer , hormone
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‐α (TNFα) is secreted from prostate cancer epithelial cells and LNCaP cells. We hypothesized that TNFα changes androgen‐sensitivity in LNCaP cells. METHODS We cultured LNCaP cells for more than 3 months in the presence of 50 ng/ml TNFα and established TNFα‐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 TNFα 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. Prostate 46:319–326, 2001. © 2001 Wiley‐Liss, Inc.