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Carcinogenesis. 2014 Nov;35(11):2592-601. doi: 10.1093/carcin/bgu183. Epub 2014 Aug 30.

PARP-1 regulates epithelial-mesenchymal transition (EMT) in prostate tumorigenesis.

Author information

1
Departments of Urology.
2
Pathology, Biochemistry, The Markey Cancer Center and.
3
Department of Toxicology, University of Kentucky College of Medicine, Lexington, KY 40535, USA.
4
Departments of Urology, Pathology, Biochemistry, The Markey Cancer Center and Department of Toxicology, University of Kentucky College of Medicine, Lexington, KY 40535, USA nkypr2@uky.edu.

Abstract

Poly (ADP-ribose) polymerase (PARP) is involved in key cellular processes such as DNA replication and repair, gene transcription, cell proliferation and apoptosis. The role of PARP-1 in prostate cancer development and progression is not fully understood. The present study investigated the function of PARP-1 in prostate growth and tumorigenesis in vivo. Functional inactivation of PARP-1 by gene-targeted deletion led to a significant reduction in the prostate gland size in young PARP-1-/- mice (6 weeks) compared with wild-type (WT) littermates. To determine the effect of PARP-1 functional loss on prostate cancer onset, PARP-1-/- mice were crossed with the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Pathological assessment of prostate tumors revealed that TRAMP+/-, PARP-1-/- mice exhibited higher grade prostate tumors compared with TRAMP+/- PARP-1+/+ (16-28 weeks) that was associated with a significantly increased proliferative index and decreased apoptosis among the epithelial cells in TRAMP+/- PARP-1-/- prostate tumors. Furthermore tumors harboring PARP-1 loss, exhibited a downregulation of nuclear androgen receptor. Impairing PARP-1 led to increased levels of transforming growth factor-β (TGF-β) and Smads that correlated with induction of epithelial-mesenchymal transition (EMT), as established by loss of E-cadherin and β-catenin and upregulation of N-cadherin and ZEB-1. Our findings suggest that impaired PARP-1 function promotes prostate tumorigenesis in vivo via TGF-β-induced EMT. Defining the EMT control by PARP-1 during prostate cancer progression is of translational significance for optimizing PARP-1 therapeutic targeting and predicting response in metastatic castration-resistant prostate cancer.

PMID:
25173886
PMCID:
PMC4216059
DOI:
10.1093/carcin/bgu183
[Indexed for MEDLINE]
Free PMC Article

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