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Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma.
O'Leary, Brianne R; Fath, Melissa A; Bellizzi, Andrew M; Hrabe, Jennifer E; Button, Anna M; Allen, Bryan G; Case, Adam J; Altekruse, Sean; Wagner, Brett A; Buettner, Garry R; Lynch, Charles F; Hernandez, Brenda Y; Cozen, Wendy; Beardsley, Robert A; Keene, Jeffery; Henry, Michael D; Domann, Frederick E; Spitz, Douglas R; Mezhir, James J.
Afiliación
  • O'Leary BR; Department of Surgery, University of Iowa, Iowa City, Iowa.
  • Fath MA; Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
  • Bellizzi AM; Department of Pathology, University of Iowa, Iowa City, Iowa.
  • Hrabe JE; Department of Surgery, University of Iowa, Iowa City, Iowa.
  • Button AM; Department of Biostatistics, University of Iowa, Iowa City, Iowa.
  • Allen BG; Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
  • Case AJ; Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
  • Altekruse S; National Cancer Institute, Bethesda, Maryland.
  • Wagner BA; Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
  • Buettner GR; Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
  • Lynch CF; Department of Epidemiology, University of Iowa, Iowa City, Iowa.
  • Hernandez BY; University of Hawaii Cancer Center, Honolulu, Hawaii.
  • Cozen W; University of Southern California, Los Angeles, California.
  • Beardsley RA; Galera Therapeutics, Malvern, Pennsylvania.
  • Keene J; Galera Therapeutics, Malvern, Pennsylvania.
  • Henry MD; Department of Microbiology, University of Iowa, Iowa City, Iowa.
  • Domann FE; Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
  • Spitz DR; Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
  • Mezhir JJ; Department of Surgery, University of Iowa, Iowa City, Iowa. Department of Radiation Oncology, University of Iowa, Iowa City, Iowa. james-mezhir@uiowa.edu.
Clin Cancer Res ; 21(7): 1741-51, 2015 Apr 01.
Article en En | MEDLINE | ID: mdl-25634994
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 PDA growth 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 significant 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Superóxido Dismutasa / Carcinoma Ductal Pancreático / Invasividad Neoplásica Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Superóxido Dismutasa / Carcinoma Ductal Pancreático / Invasividad Neoplásica Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos