Acquisition of agonistic properties of nonsteroidal antiandrogens after treatment with oncostatin M in prostate cancer cells.
OBJECTIVE
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.


METHODS
Expression of the OSM receptor-beta 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-beta 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 microM. 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.
Department of Urology, University of Innsbruck, A-6020 Innsbruck, Austria.
Sonia
S
Godoy-Tundidor
Alfred
A
Hobisch
Karina
K
Pfeil
Georg
G
Bartsch
Zoran
Z
Culig
D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002701:Chloramphenicol / Q000031:analogs & derivatives* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D017931:DNA Primers / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005485:Flutamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D009570:Nitriles; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000378:metabolism; D053677:Receptors, Oncostatin M; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014105:Tosyl Compounds; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D017931:DNA Primers; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006131:Growth Inhibitors; D015850:Interleukin-6; D009570:Nitriles; C508351:OSM protein, human; D010455:Peptides; D011944:Receptors, Androgen; D018121:Receptors, Cytokine; D053677:Receptors, Oncostatin M; D014105:Tosyl Compounds; C026822:chloramphenicol 3-acetate; D053683:Oncostatin M; C014290:hydroxyflutamide; D002701:Chloramphenicol; D005485:Flutamide; C053541:bicalutamide; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one