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Mol Cancer Ther. 2016 Nov;15(11):2722-2732. Epub 2016 Aug 17.

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models.

Author information

1
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana.
2
Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
3
Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
4
Pancreatic Cancer Signature Center, Indianapolis, Indiana.
5
Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana.
6
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
7
Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan.
8
Neurofarba Department, Section of Medicinal Chemistry, University of Florence, Florence, Italy.
9
Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
10
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
11
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.
12
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana. mfishel@iu.edu.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multifunctional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia-inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as a part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with the hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α-mediated induction of CA9. Furthermore, an ex vivo three-dimensional tumor coculture model demonstrates dramatic enhancement of APE1/Ref-1-induced cell killing upon dual targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development; therefore, these studies have the potential to direct novel PDAC therapeutic treatment. Mol Cancer Ther; 15(11); 2722-32.

PMID:
27535970
PMCID:
PMC5097013
DOI:
10.1158/1535-7163.MCT-16-0253
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Mark R. Kelley has licensed APX3330 though Indiana University Research & Technology Corporation to ApeX Therapeutics.

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