Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models
dc.contributor.author | Logsdon, Derek P. | |
dc.contributor.author | Grimard, Michelle | |
dc.contributor.author | Luo, Meihua | |
dc.contributor.author | Shahda, Safi | |
dc.contributor.author | Jiang, Yanlin | |
dc.contributor.author | Tong, Yan | |
dc.contributor.author | Yu, Zhangsheng | |
dc.contributor.author | Zyromski, Nicholas | |
dc.contributor.author | Schipani, Ernestina | |
dc.contributor.author | Carta, Fabrizio | |
dc.contributor.author | Supuran, Claudiu T. | |
dc.contributor.author | Korc, Murray | |
dc.contributor.author | Ivan, Mircea | |
dc.contributor.author | Kelley, Mark R. | |
dc.contributor.author | Fishel, Melissa L. | |
dc.contributor.department | Department of Pediatrics, School of Medicine | en_US |
dc.date.accessioned | 2017-10-24T18:08:34Z | |
dc.date.available | 2017-10-24T18:08:34Z | |
dc.date.issued | 2016-11-01 | |
dc.description.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. | en_US |
dc.eprint.version | Author's manuscript | en_US |
dc.identifier.citation | Logsdon, D. P., Grimard, M., Luo, M., Shahda, S., Jiang, Y., Tong, Y., … Fishel, M. L. (2016). Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models. Molecular Cancer Therapeutics, 15(11), 2722–2732. https://doi.org/10.1158/1535-7163.MCT-16-0253 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/14361 | |
dc.language.iso | en_US | en_US |
dc.publisher | AACR | en_US |
dc.relation.isversionof | 10.1158/1535-7163.MCT-16-0253 | en_US |
dc.relation.journal | Molecular Cancer Therapeutics | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | Author | en_US |
dc.subject | APE1 | en_US |
dc.subject | Pancreatic Cancer | en_US |
dc.subject | Cancer | en_US |
dc.title | Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models | en_US |
dc.type | Article | en_US |
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