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Oncotarget. 2017 Dec 13;9(13):10962-10977. doi: 10.18632/oncotarget.23493. eCollection 2018 Feb 16.

APE1/Ref-1 redox-specific inhibition decreases survivin protein levels and induces cell cycle arrest in prostate cancer cells.

Author information

1
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
2
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
3
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Abstract

A key feature of prostate cancer progression is the induction and activation of survival proteins, including the Inhibitor of Apoptosis (IAP) family member survivin. Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein that is essential in activating oncogenic transcription factors. Because APE1/Ref-1 is expressed and elevated in prostate cancer, we sought to characterize APE1/Ref-1 expression and activity in human prostate cancer cell lines and determine the effect of selective reduction-oxidation (redox) function inhibition on prostate cancer cells in vitro and in vivo. Due to the role of oncogenic transcriptional activators NFĸB and STAT3 in survivin protein expression, and APE1/Ref-1 redox activity regulating their transcriptional activity, we assessed selective inhibition of APE1/Ref-1's redox function as a novel method to halt prostate cancer cell growth and survival. Our study demonstrates that survivin and APE1/Ref-1 are significantly higher in human prostate cancer specimens compared to noncancerous controls and that APE1/Ref-1 redox-specific inhibition with small molecule inhibitor, APX3330 and a second-generation inhibitor, APX2009, decreases prostate cancer cell proliferation and induces cell cycle arrest. Inhibition of APE1/Ref-1 redox function significantly reduced NFĸB transcriptional activity, survivin mRNA and survivin protein levels. These data indicate that APE1/Ref-1 is a key regulator of survivin and a potentially viable target in prostate cancer.

KEYWORDS:

APE1/Ref-1; NFκB signaling; prostate cancer; redox regulation; survivin

Conflict of interest statement

CONFLICTS OF INTEREST Mark R. Kelley has licensed APX3330 through Indiana University Research and Technology Corporation to Apexian Pharmaceuticals LLC. APX2009 is a second generation compound from Apexian Pharmaceuticals. Apexian Pharmaceuticals had neither control nor oversight of the studies, interpretation, or presentation of the data in this manuscript.

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