論文

査読有り 国際誌
2019年2月

PDCD4 Is an Androgen-Repressed Tumor Suppressor that Regulates Prostate Cancer Growth and Castration Resistance.

Molecular cancer research : MCR
  • Kenji Zennami
  • ,
  • Su Mi Choi
  • ,
  • Ross Liao
  • ,
  • Ying Li
  • ,
  • Wikum Dinalankara
  • ,
  • Luigi Marchionni
  • ,
  • Fatema H Rafiqi
  • ,
  • Akira Kurozumi
  • ,
  • Koji Hatano
  • ,
  • Shawn E Lupold

17
2
開始ページ
618
終了ページ
627
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/1541-7786.MCR-18-0837

Androgen receptor (AR) transcriptional activity contributes to prostate cancer development and castration resistance. The growth and survival pathways driven by AR remain incompletely defined. Here, we found PDCD4 to be a new target of AR signaling and a potent regulator of prostate cancer cell growth, survival, and castration resistance. The 3' untranslated region of PDCD4 is directly targeted by the androgen-induced miRNA, miR-21. Androgen treatment suppressed PDCD4 expression in a dose responsive and miR-21-dependent manner. Correspondingly, AR inhibition dose-responsively induced PDCD4 expression. Using data from prostate cancer tissue samples in The Cancer Genome Atlas (TCGA), we found a significant and inverse correlation between miR-21 and PDCD4 mRNA and protein levels. Higher Gleason grade tumors exhibited significantly higher levels of miR-21 and significantly lower levels of PDCD4 mRNA and protein. PDCD4 knockdown enhanced androgen-dependent cell proliferation and cell-cycle progression, inhibited apoptosis, and was sufficient to drive androgen-independent growth. On the other hand, PDCD4 overexpression inhibited miR-21-mediated growth and androgen independence. The stable knockdown of PDCD4 in androgen-dependent prostate cancer cells enhanced subcutaneous tumor take rate in vivo, accelerated tumor growth, and was sufficient for castration-resistant tumor growth. IMPLICATIONS: This study provides the first evidence that PDCD4 is an androgen-suppressed protein capable of regulating prostate cancer cell proliferation, apoptosis, and castration resistance. These results uncover miR-21 and PDCD4-regulated pathways as potential new targets for castration-resistant prostate cancer.

リンク情報
DOI
https://doi.org/10.1158/1541-7786.MCR-18-0837
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/30518628
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359980

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