This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Godoy-Tundidor, S. Articles by Culig, Z. Search for Related Content PubMed PubMed Citation Articles by Godoy-Tundidor, S. Articles by Culig, Z.

Acquisition of Agonistic Properties of Nonsteroidal Antiandrogens after Treatment with Oncostatin M in Prostate Cancer Cells¹

Department of Urology, University of Innsbruck, A-6020 Innsbruck, Austria (S. G-T., A. H., K. P., G. B., Z. C.), and Department of Urology, General Hospital Feldkirch, A-6800 Feldkirch, Austria (A. H.)

Purpose: Interleukin-6 (IL-6), a proinflammatory cytokine the serum andtissue levels of which are elevated in prostate cancer patients, activates the androgen receptor (AR) in a ligand-independent and synergistic manner. Oncostatin M (OSM) is an IL-6 type cytokine that regulates the growth of prostate cancer cells in a paracrine fashion. The present study was designed to investigate the regulation of AR expression and function by OSM, as well as the efficacy of the nonsteroidal antiandrogens hydroxyflutamide and bicalutamide in the inhibition of AR-mediated signal transduction.

Experimental Design: Expression of the OSM receptor-ß in the prostate cancer cell lines LNCaP, PC-3, and DU-145 was investigated by reverse transcription-PCR. DU-145 and PC-3 cells were cotransfected with an androgen-responsive gene and AR cDNA. Reporter gene activity was measured after treatment with androgen and/or OSM in the absence or presence of antiandrogens or protein kinase inhibitors. AR expression after OSM treatment was assessed by Western blot.

Results: OSM receptor-ß expression was higher in DU-145 and PC-3 than in LNCaP cells. OSM caused ligand-independent activation of the AR in DU-145 cells, and the maximal activation was 62% of that induced by the synthetic androgen methyltrienolone. In the presence of OSM, hydroxyflutamide behaved as an AR agonist. Bicalutamide down-regulated AR activation caused by OSM only at a concentration of 1 µM. The inhibitor of the protein kinase A signaling pathway PKI and dn signal transducers and activators of transcription (STAT) 3 showed no effect on AR activation by OSM. The inhibitor of the MAPK pathway, PD 98059, caused only a minor down-regulation of OSM-induced reporter gene activity. OSM did not change AR expression in DU-145 cells transfected with AR cDNA.

Conclusions: OSM is a member of the IL-6 family of cytokines, which causes ligand-independent activation of the AR without altering receptor expression. In contrast to AR activation by IL-6, nonsteroidal AR antagonists act as agonists in the presence of OSM. This may be attributable to recruitment of different intermediary signal transduction proteins by OSM and IL-6, respectively. The acquisition of agonistic properties of AR blockers in the presence of OSM might compromise use of these drugs in prostate cancer treatment.

This article has been cited by other articles:

				Z Culig, H Steiner, G Bartsch, and A Hobisch Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours Endocr. Relat. Cancer, June 1, 2005; 12(2): 229 - 244. [Abstract] [Full Text] [PDF]

				R. Foley, D. Hollywood, and M. Lawler Molecular pathology of prostate cancer: the key to identifying new biomarkers of disease Endocr. Relat. Cancer, September 1, 2004; 11(3): 477 - 488. [Abstract] [Full Text] [PDF]