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Switch from Antagonist to Agonist of the Androgen Receptor Bicalutamide is Associated with Prostate Tumour Progression in a New Model System

Overview
Journal Br J Cancer
Specialty Oncology
Date 1999 Sep 25
PMID 10496349
Citations 165
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Abstract

Advanced prostate cancer is treated by androgen ablation and/or androgen receptor (AR) antagonists. In order to investigate the mechanisms relevant to the development of therapy-resistant tumours, we established a new tumour model which closely resembles the situation in patients who receive androgen ablation therapy. Androgen-sensitive LNCaP cells were kept in androgen-depleted medium for 87 passages. The new LNCaP cell subline established in this manner, LNCaP-abl, displayed a hypersensitive biphasic proliferative response to androgen until passage 75. Maximal proliferation of LNCaP-abl cells was achieved at 0.001 nM of the synthetic androgen methyltrienolone (R1881), whereas 0.01 nM of this compound induced the same effect in parental cells. At later passages (> 75), androgen exerted an inhibitory effect on growth of LNCaP-abl cells. The non-steroidal anti-androgen bicalutamide stimulated proliferation of LNCaP-abl cells. AR protein expression in LNCaP-abl cells increased approximately fourfold. The basal AR transcriptional activity was 30-fold higher in LNCaP-abl than in LNCaP cells. R1881 stimulated reporter gene activity in LNCaP-abl cells even at 0.01 nM, whereas 0.1 nM of R1881 was needed for induction of the same level of reporter gene activity in LNCaP cells. Bicalutamide that acts as a pure antagonist in parental LNCaP cells showed agonistic effects on AR transactivation activity in LNCaP-abl cells and was not able to block the effects of androgen in these cells. The non-steroidal AR blocker hydroxyflutamide exerted stimulatory effects on AR activity in both LNCaP and LNCaP-abl cells; however, the induction of reporter gene activity by hydroxyflutamide was 2.4- to 4-fold higher in the LNCaP-abl subline. The changes in AR activity were associated neither with a new alteration in AR cDNA sequence nor with amplification of the AR gene. Growth of LNCaP-abl xenografts in nude mice was stimulated by bicalutamide and repressed by testosterone. In conclusion, our results show for the first time that the nonsteroidal anti-androgen bicalutamide acquires agonistic properties during long-term androgen ablation. These findings may have repercussions on the natural course of prostate cancer with androgen deprivation and on strategies of therapeutic intervention.

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References
1.
Miyamoto H, Yeh S, Wilding G, Chang C . Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells. Proc Natl Acad Sci U S A. 1998; 95(13):7379-84. PMC: 22623. DOI: 10.1073/pnas.95.13.7379. View

2.
Froesch B, Takayama S, Reed J . BAG-1L protein enhances androgen receptor function. J Biol Chem. 1998; 273(19):11660-6. DOI: 10.1074/jbc.273.19.11660. View

3.
JENG M, Shupnik M, Bender T, Westin E, Bandyopadhyay D, Kumar R . Estrogen receptor expression and function in long-term estrogen-deprived human breast cancer cells. Endocrinology. 1998; 139(10):4164-74. DOI: 10.1210/endo.139.10.6229. View

4.
Stone K, Mickey D, Wunderli H, MICKEY G, Paulson D . Isolation of a human prostate carcinoma cell line (DU 145). Int J Cancer. 1978; 21(3):274-81. DOI: 10.1002/ijc.2910210305. View

5.
KAIGHN M, Narayan K, Ohnuki Y, Lechner J, Jones L . Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest Urol. 1979; 17(1):16-23. View