Extracellular Superoxide and the Growth of Pancreatic Carcinoma

Title:Extracellular Superoxide and the Growth of Pancreatic Carcinoma

Volume: 9 Issue: 4

Author(s): John A. Cieslak and Joseph J. Cullen

Affiliation:

Keywords: Superoxide, pancreatic cancer, superoxide dismutase, hypoxia-inducible factor-1α.

Abstract: Adenocarcinoma of the pancreas is the fourth leading cause of cancer-related death in the United States. Therapeutic responsiveness of pancreatic cancer to surgery, chemotherapy, and radiation therapy is poor, resulting in a dismal 5-year survival of less than 3%. Point mutation of the K-ras oncogene is a common event in the early development of pancreatic cancer. Indeed, K-ras mutations occur in up to 95% of pancreatic cancers, with a resulting overall increase in production of reactive oxygen species (ROS) through the activation of NADPH oxidase (NOX). Specifically, the extracellular (non-mitochondrial) generation of superoxide (O₂^.-) from the NOX system results in cell growth and tumor progression. Extracellular superoxide dismutase (SOD3, EcSOD) is the only isoform of superoxide dismutase (SOD) expressed extracellularly. It modulates ROS by converting O₂^.- into hydrogen peroxide (H₂O₂). Antioxidant enzymes that scavenge specific ROS have inhibited the in vitro and in vivo growth of pancreatic cancer. It has been demonstrated that overexpression of EcSOD inhibits pancreatic cancer cell growth and intracellular signaling pathways. Therefore, we propose that strategies to scavenge non-mitochondrial-generated superoxide may prove beneficial in the treatment pancreatic cancer. This review will focus on the role of O₂^.- as a pro-tumorigenic signaling molecule, including its generation and hypothesized mechanism of action, as well as the role of EcSOD in inhibiting tumor growth and propagation, and its potential as a targeted pancreatic cancer therapy.

Cite this article as:

A. Cieslak John and J. Cullen Joseph, Extracellular Superoxide and the Growth of Pancreatic Carcinoma, Current Cancer Therapy Reviews 2013; 9 (4) . https://dx.doi.org/10.2174/157339470904140418095056