title: PARP-1 regulates epithelial-mesenchymal transition (EMT) in prostate tumorigenesis.
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.
authors.affiliation: Departments of Urology.
authors.forename: Hong
authors.initials: H
authors.lastname: Pu
authors.affiliation: Pathology, Biochemistry, The Markey Cancer Center and.
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
authors.affiliation: Departments of Urology.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Hensley
authors.affiliation: Department of Toxicology, University of Kentucky College of Medicine, Lexington, KY 40535, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Matuszak
authors.affiliation: Departments of Urology.
authors.forename: Timothy
authors.initials: T
authors.lastname: Atkinson
authors.affiliation: 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.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kyprianou
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; D016212:Transforming Growth Factor beta; D051176:beta Catenin; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases