Effect of type I growth factor receptor tyrosine kinase inhibitors on phosphorylation and transactivation activity of the androgen receptor in prostate cancer cells: Ligand-independent activation of the N-terminal domain of the androgen receptor.
Although there have been several studies suggesting the involvement of growth factor receptor tyrosine kinases in ligand-independent activation of the androgen receptor (AR) and progression of prostate cancer, limited studies have been reported actually showing the enhancement of phosphorylation of the AR in vivo in response to growth factors or activation of their receptors in prostate cancer cells. In this study, we have demonstrated that overexpression of HER2/Neu enhanced in vivo phosphorylation of the AR and MAP kinase in DU-145 cells, and that the HER2/Neu inhibitor TAK165 reduced the HER2/Neu-enhanced phosphorylated AR and MAP kinase, indicating that the MAP kinase pathway seems to be involved in the phosphorylation of the AR by HER2/Neu. Both HER2/Neu inhibitor TAK165 and EGFR tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) successfully reduced the HER2/Neu-induced transactivation activity of the AR in PC-3 and DU-145 cells, suggesting that these inhibitors are possible therapeutic drugs for patients with hormone-refractory prostate cancer. The transactivation activity of the AF-1+DBD of the AR was enhanced by HER2/Neu overexpression while that of the AF-2+DBD was not, demonstrating that the enhancement of the AR activity by HER2/Neu was mainly mediated through the AF-1 of the AR.
Sugita
Shozo
S
Department of Urology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan.
Kawashima
Hidenori
H
Tanaka
Tomoaki
T
Kurisu
Takeshi
T
Sugimura
Kazunobu
K
Nakatani
Tatsuya
T
D000728:Androgens / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D000728:Androgens; D004791:Enzyme Inhibitors; D000077156:Gefitinib; D008024:Ligands; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; D015534:Trans-Activators