P20 - 2018 SFRBM LIFETIME ACHIEVEMENT AWARD LECTURE MnSOD at the Crossroads of Life and Death: We've Only Just Begun

Abstract

Manganese superoxide dismutase (MnSOD), a mitochondria-localized primary antioxidant enzyme, is essenstial for the survival of all areobic life. Decades of research on MnSOD have extended our understanding of the role of superoxide radicals and their associated reactive oxygen derived species (ROS) in mitochondria well beyond the once prevalent view of their being the toxic byproducts of cellular energy production to include their being important in cell signaling. Our studies on the regulation of MnSOD expression during cancer development and progression have contributed to the knowledge that cancer cells are usually under higher oxidative stress conditions than normal cells are and that different redox potentials can trigger different responses. A low redox potential triggers survival pathways, whereas a high redox potential triggers cell death mediators. This results in a therapeutic window in which redox-active antioxidants can manipulate intracellular redox stress levels that induce normal cells to produce prosurvival responses while cancer cells produce, on the other hand, lethal responses. These antioxidant/prooxidant properties are best represented by MnSOD, which cycles active site manganese through varying states of oxidation. Thus, overexpression of MnSOD in normal tissues protects tissues against oxidative stress-induced injury, which includes protection of cardiac function from the influences of the anticancer drug doxorubicin, lung fibrosis from ionizing radiation, and brain damage from beta amyloid. In contrast, overexpression of MnSOD in malignant cells results in reduced cancer cell survival. Identification of these paradoxical properties of MnSOD has led to the development of potential therapeutics that are capable of acting as redox active oxidants or of mimicking endogenous enzyme functions. This presentation introduces the prospect of a novel avenue to therapeutic control using redox active antioxidants. It also introduces a novel redox-based liquid biopsy approach that uses oxidatively modified extracellular vesicles (EVs) as mediators of therapy-induced normal tissue injury and prognosis markers of cancer responses to therapy. Our expectation is that the results from extensive proof-of-concept studies, coupled with an in-depth understanding of the mechanisms mediating this exciting concept, will lead to further developments of novel redox- based therapeutic agents for clinical applications.