A study on the mechanism by which ligand-independent activation of the androgen receptor occurs in hormone-refractory prostate cancer

• Project/Area Number: 15591707
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Osaka City University
• Principal Investigator: KAWASHIMA Hidenori Osaka City University, Graduate School of Medicine Urology, Assistant Professor, 大学院・医学研究科, 講師 (70234060)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥2,500,000 (Direct Cost: ¥2,500,000); Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
• Keywords: androgen receptor / hormone-refractory prostate cancer / type I growth factor receptor / HFR2 / Neu / MAP kinase / activation function-1 / gefitinib / TAK165 / activation fonction-1 / Her2 / phosphorylation

Research Abstract

Although there have been several reports 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 demonstrating 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 shown that overexpression of HER2/Neu enhanced in vivo-phosphorylation of the AR and that of MAP kinase in DU-145 cells, and that the HER2/Neu inhibitor TAK165 reduced the HER2/Neu-enhanced phosphorylation of 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, indicating that these inhibitors are possible therapeutic drugs for patients with hormone-refractory prostate cancer. The transactivation activity of the N-terminal domain (AF-1+DBD) of the AR was enhanced by HER2/Neu overexpression while that of the ligand-binding domain (AF-2+DBD) was not, demonstrating that the enhancement of the AR activity by HER2/Neu was mainly mediated through the N-terminal domain (AF-1) of the AR.

Research Products

• [Journal Article] Effect of type I growth factor receptor tyrosine kinase inhibitors on phosphorylation and transactivation activity of the androgen receptor in prostate cancer cell (2004)
  • Author(s): Sugita S, Kawashima H, Tanaka T, Kurisu T, Sugimura K, Nakatani T
  • Journal Title: Oncology Reports 11 Pages: 1273-1279
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of anti-estrogens on the androgen receptor activity an d cell proliferation in prostate cancer cells (2004)
  • Author(s): Kawashima H, Tanaka T, Cheng J-S, Sugita S, Ezaki K, Kurisu T et al.
  • Journal Title: Urological Research 32 Pages: 406-410
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 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. (2004)
  • Author(s): Sugita, S., Kawashima, H., Tanaka, T., Kurisu, T., Sugimura.K., Nakatani, T.
  • Journal Title: Oncol.Rep. 11 Pages: 1273-1279
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of anti-estrogens on the androgen receptor activity and cell proliferation in prostate cancer cells. (2004)
  • Author(s): Kawashima, H., Tanaka, T., Cheng, J.-S., Sugita, S., Ezaki, K., Kurisu, T., Nakatani, T.
  • Journal Title: Urol.Res. 32 Pages: 406-410
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of anti-estrogens on the androgen receptor activity and cell proliferation in prostate cancer cells (2004)
  • Author(s): Kawashima H, Tanaka T, Cheng J-S, Sugita S, Ezaki K, Kurisu T et al.
  • Journal Title: Urological Research 32 Pages: 406-410
• [Publications] Shozo SUGITA, Hidenori KAWASHIMA, Tomoaki TANAKA, Takeshi KURISU, Kazunobu SUGIMURA, Tatsuya NAKATANI: "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"Oncology Reports. (In press).