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Mol Cancer Res. 2019 Feb;17(2):618-627. doi: 10.1158/1541-7786.MCR-18-0837. Epub 2018 Dec 5.

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

Author information

1
Department of Urology, The James Buchanan Brady Urologic Institute, Johns Hopkins School of Medicine, Baltimore, Maryland.
2
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
3
Department of Urology, The James Buchanan Brady Urologic Institute, Johns Hopkins School of Medicine, Baltimore, Maryland. slupold@jhmi.edu.

Abstract

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.

PMID:
30518628
PMCID:
PMC6359980
[Available on 2020-02-01]
DOI:
10.1158/1541-7786.MCR-18-0837

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