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

Research output: Contribution to journalArticle

32 Scopus citations


Purpose: 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 PDAgrowth and invasion by modifying the redox balance in PDA. Experimental Design: 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. Results: 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 signi ficant decreases in PDA cell invasive capacity. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)1741-1751
Number of pages11
JournalClinical Cancer Research
Issue number7
StatePublished - Apr 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Loss of SOD3 (EcSOD) expression promotes an aggressive phenotype in human pancreatic ductal adenocarcinoma'. Together they form a unique fingerprint.

  • Cite this

    O'Leary, B. R., Fath, M. A., Bellizzi, A. M., Hrabe, J. E., Button, A. M., Allen, B. G., Case, A. J., Altekruse, S., Wagner, B. A., Buettner, G. R., Lynch, C. F., Hernandez, B. Y., Cozen, W., Beardsley, R. A., Keene, J., Henry, M. D., Domann, F. E., Spitz, D. R., & Mezhir, J. J. (2015). Loss of SOD3 (EcSOD) expression promotes an aggressive phenotype in human pancreatic ductal adenocarcinoma. Clinical Cancer Research, 21(7), 1741-1751. https://doi.org/10.1158/1078-0432.CCR-14-1959