Switch from antagonist to agonist of the androgen receptor blocker bicalutamide is associated with prostate tumour progression in a new model system

被引：337

作者：

Culig Z. ^{[1
]}

Hoffmann J. ^{[4
]}

Erdel M. ^{[2
]}

Eder I.E. ^{[1
]}

Hobisch A. ^{[1
]}

Hittmair A. ^{[3
]}

Bartsch G. ^{[1
]}

Utermann G. ^{[2
]}

Schneider M.R. ^{[4
]}

Parczyk K. ^{[4
]}

Klocker H. ^{[1
]}

机构：

[1] Department of Urology, University of Innsbruck, A-6020 Innsbruck

[2] Dept. of Med. Biol. and Hum. Genet., University of Innsbruck, A-6020 Innsbruck

[3] Department of Pathology, University of Innsbruck, A-6020 Innsbruck

[4] Research Laboratories of Schering AG

来源：

British Journal of Cancer | 1999年 / 81卷 / 2期

基金：

奥地利科学基金会;

关键词：

Androgen ablation; Androgen receptor; Bicalutamide; LNCaP cells; Prostate cancer; Tumour progression;

D O I：

10.1038/sj.bjc.6690684

中图分类号：

学科分类号：

摘要：

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.

引用

页码：242 / 251

页数：9

共 44 条

[1] Cher M.L., Bova G.S., Moore D.H., Small E.J., Carroll P.R., Pin S.S., Epstein J.I., Isaacs W.B., Jensen R.H., Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping, Cancer Res, 56, pp. 3091-3102, (1996)
[2] Culig Z., Hobisch A., Cronauer M.V., Cato A.C.B., Hittmair A., Radmayr C., Eberle J., Bartsch G., Klocker H., Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone, Mol Endocrinol, 7, pp. 1541-1550, (1993)
[3] Culig Z., Klocker H., Eberle J., Kaspar F., Hobisch A., Cronauer M.V., Bartsch G., DNA sequence of the androgen receptor in prostatic tumor cell lines and tissue specimens assessed by means of the polymerase chain reaction, Prostate, 22, pp. 11-22, (1993)
[4] Culig Z., Hobisch A., Cronauer M.V., Radmayr C., Trapman J., Hittmair A., Bartsch G., Klocker H., Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor, Cancer Res, 54, pp. 5474-5478, (1994)
[5] Cronauer M.V., Klocker H., Talasz H., Geisen F.H., Hobisch A., Radmayr C., Bock G., Culig Z., Schirmer M., Reissigl A., Bartsch G., Konwalinka G., Inhibitory effects of the nucleoside analogue gemcitabine on prostatic carcinoma cells, Prostate, 28, pp. 172-181, (1996)
[6] Culig Z., Hobisch A., Hittmair A., Cronauer M.V., Radmayr C., Zhang J., Bartsch G., Klocker H., Synergistic activation of androgen receptor by androgen and luteinizing hormone-releasing hormone in prostatic carcinoma cells, Prostate, 32, pp. 106-114, (1997)
[7] Culig Z., Hobisch A., Hittmair A., Cronauer M.V., Radmayr C., Bartsch G., Klocker H., Androgen receptor gene mutations in prostate cancer. Implications for disease progression and therapy, Drugs Aging, 10, pp. 50-58, (1997)
[8] Dijkman G.A., Debruyne F.M., Epidemiology of prostate cancer, Eur Urol, 30, pp. 281-298, (1996)
[9] Froesch B.A., Takayama S., Reed J.C., BAG-1L protein enhances androgen receptor function, J Biol Chem, 273, pp. 11660-11666, (1998)
[10] Gibas Z., Becher R., Kawinski E., Horoszewicz J., Sandberg A.A., A high-resolution study of chromosome changes in a human prostate carcinoma cell line, Cancer Genet Cytogenet, 2, pp. 399-404, (1984)

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