Androgen receptor and poly(ADP-ribose) glycohydrolase inhibition increases efficiency of androgen ablation in prostate cancer cells
James, Dominic I
Smith, Kate M
Waddell, Ian D
Ogilvie, Donald J
AffiliationBiochemistry Ph.D. Program, Florida International University, Miami, FL,
MetadataShow full item record
AbstractThere is mounting evidence of androgen receptor signaling inducing genome instability and changing DNA repair capacity in prostate cancer cells. Expression of genes associated with base excision repair (BER) is increased with prostate cancer progression and correlates with poor prognosis. Poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) are key enzymes in BER that elongate and degrade PAR polymers on target proteins. While PARP inhibitors have been tested in clinical trials and are a promising therapy for prostate cancer patients with TMPRSS2-ERG fusions and mutations in DNA repair genes, PARG inhibitors have not been evaluated. We show that PARG is a direct androgen receptor (AR) target gene. AR is recruited to the PARG locus and induces PARG expression. Androgen ablation combined with PARG inhibition synergistically reduces BER capacity in independently derived LNCaP and LAPC4 prostate cancer cell lines. A combination of PARG inhibition with androgen ablation or with the DNA damaging drug, temozolomide, significantly reduces cellular proliferation and increases DNA damage. PARG inhibition alters AR transcriptional output without changing AR protein levels. Thus, AR and PARG are engaged in reciprocal regulation suggesting that the success of androgen ablation therapy can be enhanced by PARG inhibition in prostate cancer patients.
CitationZhang M, Lai Y, Vasquez JL, James DI, Smith KM, Waddell ID, et al. Androgen Receptor and Poly(ADP-ribose) Glycohydrolase Inhibition Increases Efficiency of Androgen Ablation in Prostate Cancer Cells. Sci Rep. 2020;10:3836.
- Targeting poly(ADP-ribose) glycohydrolase to draw apoptosis codes in cancer.
- Authors: Tanuma SI, Shibui Y, Oyama T, Uchiumi F, Abe H
- Issue date: 2019 Sep
- Inhibition of poly(ADP-ribose) polymerase-1 or poly(ADP‑ribose) glycohydrolase individually, but not in combination, leads to improved chemotherapeutic efficacy in HeLa cells.
- Authors: Feng X, Koh DW
- Issue date: 2013 Feb
- Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase.
- Authors: Gravells P, Grant E, Smith KM, James DI, Bryant HE
- Issue date: 2017 Apr
- Global analysis of transcriptional regulation by poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in MCF-7 human breast cancer cells.
- Authors: Frizzell KM, Gamble MJ, Berrocal JG, Zhang T, Krishnakumar R, Cen Y, Sauve AA, Kraus WL
- Issue date: 2009 Dec 4
- Silencing of poly(ADP-ribose) glycohydrolase sensitizes lung cancer cells to radiation through the abrogation of DNA damage checkpoint.
- Authors: Nakadate Y, Kodera Y, Kitamura Y, Tachibana T, Tamura T, Koizumi F
- Issue date: 2013 Nov 29