Insulin-like growth factor-I induces CLU expression through Twist1 to promote prostate cancer growth

Ario Takeuchi, Masaki Shiota, Eliana Beraldi, Daksh Thaper, Kiyoshi Takahara, Naokazu Ibuki, Michael Pollak, Michael E. Cox, Seiji Naito, Martin E. Gleave, Amina Zoubeidi

研究成果: Article査読

13 被引用数 (Scopus)

抄録

Clusterin (CLU) is cytoprotective molecular chaperone that is highly expressed in castrate-resistant prostate cancer (CRPC). CRPC is also characterized by increased insulin-like growth factor (IGF)-I responsiveness which induces prostate cancer survival and CLU expression. However, how IGF-I induces CLU expression and whether CLU is required for IGF-mediated growth signaling remain unknown. Here we show that IGF-I induced CLU via STAT3-Twist1 signaling pathway. In response to IGF-I, STAT3 was phosphorylated, translocated to the nucleus and bound to the Twist1 promoter to activate Twist1 transcription. In turn, Twist1 bound to E-boxes on the CLU promoter and activated CLU transcription. Inversely, we demonstrated that knocking down Twist1 abrogated IGF-I induced CLU expression, indicating that Twist1 mediated IGF-I-induced CLU expression. When PTEN knockout mice were crossed with lit/. lit mice, the resultant IGF-I deficiency suppressed Twist1 as well as CLU gene expression in mouse prostate glands. Moreover, both Twist1 and CLU knockdown suppressed prostate cancer growth accelerated by IGF-I, suggesting the relevance of this signaling not only in an in vitro, but also in an in vivo. Collectively, this study indicates that IGF-I induces CLU expression through sequential activation of STAT3 and Twist1, and suggests that this signaling cascade plays a critical role in prostate cancer pathogenesis.

本文言語English
ページ(範囲)117-125
ページ数9
ジャーナルMolecular and Cellular Endocrinology
384
1-2
DOI
出版ステータスPublished - 25-03-2014
外部発表はい

All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子生物学
  • 内分泌学

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