The androgen receptor co-activator CBP is up-regulated following androgen withdrawal and is highly expressed in advanced prostate cancer.
The androgen receptor co-activator CREB (cAMP-response element binding protein)-binding protein (CBP) enhances androgen receptor activity after stimulation by androgenic hormones and androgen receptor antagonists. The aim of the present study was to investigate the regulation of CBP expression by steroid and peptide hormones in prostate cancer. For this purpose, LNCaP cells were treated with the synthetic androgen methyltrienolone (R1881), epidermal growth factor, insulin-like growth factor-I or interleukin-6 (IL-6). CBP protein and mRNA expression were studied by western blotting and real-time PCR, respectively. CBP expression was also investigated in tissue specimens obtained from 26 patients with therapy-resistant carcinoma of the prostate. In LNCaP cells, CBP protein was down-regulated by R1881 or IL-6. The non-steroidal anti-androgen bicalutamide antagonized the effects of R1881 and the Janus kinase inhibitor AG 490 reversed the effects of IL-6. In contrast, neither R1881 nor IL-6 caused any effect on CBP expression in the PC-3 cell line. In LNCaP cells, the inhibition of CBP expression by R1881 or IL-6 was also observed at the mRNA level. CBP protein was detected in all 26 specimens by immunohistochemistry. The results suggest that up-regulation of CBP during androgen ablation may be relevant to the failure of endocrine therapy in patients with prostate carcinoma.
Comuzzi
Barbara
B
Department of Urology, Innsbruck Medical University, A-6020 Innsbruck, Austria.
Nemes
Constanze
C
Schmidt
Stefan
S
Jasarevic
Zerina
Z
Lodde
Michele
M
Pycha
Armin
A
Bartsch
Georg
G
Offner
Felix
F
Culig
Zoran
Z
Hobisch
Alfred
A
D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D050882:CREB-Binding Protein; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D009570:Nitriles; D009687:Nuclear Proteins / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D011944:Receptors, Androgen / Q000235:genetics; D014105:Tosyl Compounds; D015534:Trans-Activators / Q000235:genetics*; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics
D000726:Androgen Antagonists; D000813:Anilides; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D009570:Nitriles; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D015741:Metribolone; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; C053541:bicalutamide; D050882:CREB-Binding Protein; C494363:CREBBP protein, human