Indiana University-Purdue University Indianapolis (IUPUI) / Continual and recalcitrant inflammation is an extremely common condition
in the human prostate and has been found to be associated with a number of
prostatic diseases including prostate cancer and benign prostatic hyperplasia
(BPH). While much has been described regarding prostate disease resulting from
oxygen and nitrogen radicals during inflammation, proliferative mechanisms
associated with repair and regeneration are less understood. The Inhibitor of
Apoptosis (IAP) family member survivin has been found to be overexpressed
during inflammation and associated with prostate cancer progression.
Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a
multifunctional protein that is essential in activating inflammatory 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
inflammatory 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 inhibitors APX3330 and 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.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/14787 |
| Date | 23 June 2017 |
| Creators | McIlwain, David W. |
| Contributors | Lu, Tao, Fishel, Melissa L., Jerde, Travis J., Mosley, Amber L., Zhang, Jian-ting |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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