Regulation of HIF1a under hypoxia by APE1/Ref-1 impacts CA9 expression: Dual targeting in patient-derived 3D pancreatic cancer models

Derek P. Logsdon, Michelle Grimard, Meihua Luo, Safi Shahda, Yanlin Jiang, Yan Tong, Zhangsheng Yu, Nicholas Zyromski, Ernestina Schipani, Fabrizio Carta, Claudiu T. Supuran, Murray Korc, Mircea Ivan, Mark R. Kelley, Melissa L. Fishel

Research output: Contribution to journalArticle

38 Scopus citations

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 (HIF1a). Carbonic anhydrase IX (CA9) is regulated by HIF1aand 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 downstreamtranscription factors, STAT3 and HIF1a, interfering with the hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1a-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.

Original languageEnglish (US)
Pages (from-to)2722-2732
Number of pages11
JournalMolecular cancer therapeutics
Volume15
Issue number11
DOIs
StatePublished - Nov 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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