Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma

Brianne R O'Leary; Melissa A Fath; Andrew M Bellizzi; Jennifer E Hrabe; Anna M Button; Bryan G Allen; Adam J Case; Sean Altekruse; Brett A Wagner; Garry R Buettner; Charles F Lynch; Brenda Y Hernandez; Wendy Cozen; Robert A Beardsley; Jeffery Keene; Michael D Henry; Frederick E Domann; Douglas R Spitz; James J Mezhir

doi:10.1158/1078-0432.CCR-14-1959

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Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma

Journal article

Open access

Peer reviewed

Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma

Brianne R O'Leary, Melissa A Fath, Andrew M Bellizzi, Jennifer E Hrabe, Anna M Button, Bryan G Allen, Adam J Case, Sean Altekruse, Brett A Wagner, Garry R Buettner, …

Clinical cancer research, Vol.21(7), pp.1741-1751

04/01/2015

DOI: 10.1158/1078-0432.CCR-14-1959

PMCID: PMC4383686

PMID: 25634994

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Abstract

Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA. We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA. Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity. These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease.

Immunohistochemistry

SEER Program

Reactive Oxygen Species

Superoxide Dismutase - biosynthesis

Tissue Array Analysis

Humans

Pancreatic Neoplasms - pathology

Carcinoma, Pancreatic Ductal - pathology

Blotting, Western

Phenotype

Animals

Heterografts

Neoplasm Invasiveness - pathology

Mice

Real-Time Polymerase Chain Reaction

Superoxide Dismutase - metabolism

Details

Title: Subtitle: Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma
Creators: Brianne R O'Leary - Department of Surgery, University of Iowa, Iowa City, Iowa
Melissa A Fath - Department of Radiation Oncology, University of Iowa, Iowa City, Iowa
Andrew M Bellizzi - Department of Pathology, University of Iowa, Iowa City, Iowa
Jennifer E Hrabe - Department of Surgery, University of Iowa, Iowa City, Iowa
Anna M Button - Department of Biostatistics, University of Iowa, Iowa City, Iowa
Bryan G Allen - Department of Radiation Oncology, University of Iowa, Iowa City, Iowa
Adam J Case - Department of Radiation Oncology, University of Iowa, Iowa City, Iowa
Sean Altekruse - National Cancer Institute, Bethesda, Maryland
Brett A Wagner - Department of Radiation Oncology, University of Iowa, Iowa City, Iowa
Garry R Buettner - Department of Radiation Oncology, University of Iowa, Iowa City, Iowa
Charles F Lynch - Department of Epidemiology, University of Iowa, Iowa City, Iowa
Brenda Y Hernandez - University of Hawaii Cancer Center, Honolulu, Hawaii
Wendy Cozen - University of Southern California, Los Angeles, California
Robert A Beardsley - Galera Therapeutics, Malvern, Pennsylvania
Jeffery Keene - Galera Therapeutics, Malvern, Pennsylvania
Michael D Henry - Department of Microbiology, University of Iowa, Iowa City, Iowa
Frederick E Domann - Department of Radiation Oncology, University of Iowa, Iowa City, Iowa
Douglas R Spitz - Department of Radiation Oncology, University of Iowa, Iowa City, Iowa
James J Mezhir - Department of Surgery, University of Iowa, Iowa City, Iowa. Department of Radiation Oncology, University of Iowa, Iowa City, Iowa. james-mezhir@uiowa.edu
Resource Type: Journal article
Publication Details: Clinical cancer research, Vol.21(7), pp.1741-1751
DOI: 10.1158/1078-0432.CCR-14-1959
PMID: 25634994
PMCID: PMC4383686
NLM abbreviation: Clin Cancer Res
ISSN: 1078-0432
eISSN: 1557-3265
Publisher: United States
Grant note: P30 ES005605 / NIEHS NIH HHS T32 CA078586 / NCI NIH HHS T32 CA148062 / NCI NIH HHS N01-PC-35137 / NCI NIH HHS F32 HL122021 / NHLBI NIH HHS R01 CA115438 / NCI NIH HHS R01 CA182804 / NCI NIH HHS R01CA133114 / NCI NIH HHS N01PC35139 / NCI NIH HHS R21 CA161182 / NCI NIH HHS R01 CA133114 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA130916 / NCI NIH HHS N01PC35137 / NCI NIH HHS R01 CA169046 / NCI NIH HHS P30 CA071789 / NCI NIH HHS R21CA161182 / NCI NIH HHS N01PC35143 / NCI NIH HHS T32CA148062 / NCI NIH HHS N01-PC-35139 / NCI NIH HHS N01 PC035137 / NCI NIH HHS N01-PC-35143 / NCI NIH HHS
Language: English
Date published: 04/01/2015
Academic Unit: Molecular Physiology and Biophysics; Epidemiology; Pathology; Surgery; Radiation Oncology; Urology
Record Identifier: 9983996063102771

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