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.

Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis

“…Of note, the role of PARP-1 in fibrosis may differ depending on the affected organ systems. In internal organs such as liver, lungs and kidneys, most publications report that PARP-1 promotes epithelial-to-mesenchymal transition (EMT) and fibrosis,34–38 while other studies report exacerbation of EMT by inhibition of PARP-1 39. Consistent with the different outcomes in fibrosis, inhibitory as well as stimulatory effects of PARP-1 on TGFβ/Smad signalling have been reported in vitro 15 16 37 39–41.…”

Anoikis and EMT: Lethal "Liaisons" during Cancer Progression

“…68 Acquisition of the mesenchymal phenotype is functionally associated with the ability to overcome anoikis. 69 Growing evidence links EMT induction to apoptosis evasion via upregulation of Bcl-2 antiapoptotic proteins and/or activation of the PI3-K/Akt prosurvival pathways, often associated with the downregulation of proapoptotic proteins such as Bim, Bax, Noxa, p21, and p53 effector related to pmp22Y. 70–72 …”

Inhibition of Epithelial-to-Mesenchymal Transition (EMT) by Hyperthermia

“…11.6) [25]. In BxPC-3 cells, no significant change in Snail expression was observed after exposure to TGF-β1 or hyperthermia; this caused us to investigate ZEB-1 expression in BxPC-3 cells [26][27][28]. We observed that ZEB-1 expression was upregulated by TGF-β1 treatment in BxPC-3 cells; this upregulation was then significantly blocked by hyperthermia ( Fig.…”