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

David W Mcilwain,Mark R Kelley,Alexander Boos,Melissa L Fishel,Travis J Jerde

doi:10.18632/oncotarget.23493

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.

Highlights

Prostate cancer (PCa) is one of the most common male malignancies and the third leading cause of cancerrelated death of men in the United States [1,2]
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
APE1/Ref-1 and survivin are nuclear and cytoplasmic localized in human prostate cancer

Summary

Introduction

Prostate cancer (PCa) is one of the most common male malignancies and the third leading cause of cancerrelated death of men in the United States [1,2]. Some men develop an aggressive phenotype that metastasizes and becomes incurable once colonizing the bone [6,7] These bone metastases produce osteoblastic lesions that are associated with high morbidity and high mortality [8] and attempts at delaying this tumor progression with chemotherapeutic agents have only prolonged survival a few months. [9,10] In order to create more effective treatments where conventional therapeutics have failed, a better understanding of the aggressive phenotype of the disease is of utmost importance and a great unmet medical need It is well-established that reduction-oxidation (redox) regulation of critical transcriptional activators plays an essential role in cell proliferation and survival in a number of different cancers, including prostate cancer [11,12,13]. The blockade of APE1/Ref-1’s redox activity has been shown to reduce growth-promoting, inflammatory and anti-apoptotic activities in cells [24,25]

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