Research Abstract

A normal result of cellular metabolism is the production of highly reactive forms of oxygen called oxidants. These oxidants under physiologic circumstances have important roles in many cellular activities. The normal balance of oxidants in cells is maintained by the interaction of processes that produce oxidants and processes that reduce oxidants, called antioxidants. The principal antioxidant in all cells is the compound NADPH. The principal source of NADPH for the antioxidant system is glucose 6-phosphate dehydrogenase (G6PD), which is the rate-limiting enzyme of the pentose phosphate pathway. Traditionally researchers have focused on the role of G6PD in lipid metabolism and the role of G6PD in G6PD deficient-associated hemolytic anemia. Moreover, scientists thought that G6PD was a classic “housekeeping gene” that was not highly regulated. Discoveries from the laboratory of Robert C. Stanton, M.D., have shown that G6PD is a highly regulated enzyme. Research revealed that G6PD is regulated by growth factors, glucose level, aldosterone, and many other factors. Research from the laboratory has elucidated intracellular signaling molecules that regulate G6PD at the transcriptional and post-translational level. Dr. Stanton’s laboratory has also determined that G6PD is central to the health of all cells being essential for cell survival. Additionally, discoveries from Dr. Stanton’s laboratory have demonstrated that decreases in G6PD activity lead to impaired function of multiple cellular systems that depend on NADPH and ultimately cell death. Many other laboratories around the world have used our research to study the role and regulation of G6PD in cancer, diabetes, and other diseases. Importantly virtually all cancers have significant increases in G6PD activity and alterations in oxidant metabolism that play major roles in cancer cell development and metastases. Thus the laboratory studies how G6PD is regulated, the roles and importance of G6PD in cell growth and cell death, and how to alter G6PD activity to design new treatments aimed to treat such diseases as cancer and diabetes. Current studies are also focused on elucidating the role of G6PD and associated proteins in the regulation of all aspects of oxidant metabolism in normal physiology and in pathophysiologic conditions.