PDCD4 is an androgen-repressed tumor suppressor that regulates prostate cancer growth and castration resistance

Kenji Zennami, Su Mi Choi, Ross Liao, Ying Li, Wikum Dinalankara, Luigi Marchionni, Fatema H. Rafiqi, Akira Kurozumi, Koji Hatano, Shawn E. Lupold

研究成果: Article査読

13 被引用数 (Scopus)

抄録

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 castrationresistant 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.

本文言語English
ページ(範囲)618-627
ページ数10
ジャーナルMolecular Cancer Research
17
2
DOI
出版ステータスPublished - 02-2019
外部発表はい

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 腫瘍学
  • 癌研究

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