Indiana University-Purdue University Indianapolis (IUPUI) / Pancreatic ductal adenocarcinoma (PDAC) is an extremely deadly disease
characterized by aggressive metastasis and therapeutic resistance. Reactive stroma in
pancreatic tumors contributes to tumor signaling, fibrosis, inflammation, and hypoxia.
Hypoxia signaling creates a more aggressive phenotype with increased potential for
metastasis and decreased therapeutic efficacy. Carbonic anhydrase IX (CA9) functions as
part of the cellular response to hypoxia by regulating intracellular pH to promote cell
survival. Apurinic/Apyrimidinic Endonuclease-1-Reduction/oxidation Effector Factor 1
(APE1/Ref-1) is a multi-functional protein with two major activities: endonuclease activity
in DNA base excision repair and a redox signaling activity that reduces oxidized
transcription factors, enabling them to bind target sequences in DNA. APE1/Ref-1 is a
central node in redox signaling, contributing to the activation of transcription factors
involved in tumor survival, growth, and hypoxia signaling. This work evaluates the
mechanisms underlying PDAC cell responses to hypoxia and APE1/Ref-1 redox signaling
control of hypoxia inducible factor 1 alpha (HIF1a), a critical factor in hypoxia-induced
CA9 transcription. We hypothesized that obstructing the HIF-CA9 axis at two points via APE1/Ref-1 inhibition and CA9 inhibition results in enhanced PDAC cell killing under
hypoxic conditions.
We found that HIF1a-mediated induction of CA9 is significantly attenuated
following APE1/Ref-1 knock-down or redox signaling inhibition in patient-derived PDAC
cells and pancreatic cancer-associated fibroblast cells. Additionally, dual-targeting of
APE1/Ref-1 redox signaling activity and CA9 activity results in enhanced acidification and
cytotoxicity of PDAC cells under hypoxic conditions as well as decreased tumor growth in
an ex-vivo 3-dimensional tumor co-culture model. Further experiments characterized
novel analogs of clinically relevant drugs targeting the key enzymes in this pathway,
resulting in improved potency. These results underscore the notion that combination
therapy is essential and demonstrate the potential clinical utility of blocking APE1/Ref-1
and CA9 function for novel PDAC therapeutic treatment.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/15833 |
| Date | 14 December 2017 |
| Creators | Logsdon, Derek Paul |
| Contributors | Kelly, Mark, Fishel, Melissa, Jerde, Travis, Vasko, Michael, Fehrenbacher, Jill |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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