The contribution of phosphorylated Rac (Ser-71) and subsequent NADPH oxidase signaling to colon cancer developemnt
Final Report Abstract
NADPH oxidases (also called “Nox”) are proteins that reside in the membrane of cells. Nox play a key role in catalyzing the reduction of oxygen (O2) to form Reactive Oxygen Species (ROS) including superoxide anion (O2·-), hydrogen peroxide (H2O2), and hydroxyl radical (OH·). The balance between ROS production and removal by antioxidants (scavenger) regulates the role of ROS in cells. At low to moderate levels, ROS play an important role in cell signaling processes such as cell division/multiplication (proliferation), transformation, cell death (apoptosis), differentiation, and migration. But at high concentrations, ROS chemically react with biological molecules (lipids, protein, DNA) and can contribute directly to tissue damage. This mechanism has been linked to a number of diseases, including cancer. Most Noxrelated diseases are mediated by a single member of the Nox family, which includes seven known members (Nox1 to Nox5, Duox1 and Duox2). Specifically, ROS generated by Nox1 has been associated with colon cancer. In my research work, I investigated how an alteration in the amino acid sequence of Rac1 (serine for glutamate which mimics phosphorylation at serine 71) affects its regulatory role in controlling Nox activity. The result of this is that phosphorylated Rac1 positively impacts the amount of Nox1-dependent ROS. As dysregulation of ROS is known to cause cancer growth, the discovery of this mechanism can be used to better understand the (Phospho) Rac1-Nox1-ROS pathway and can be used to develop new drugs blocking the phosphorylation of Rac1 and thereby ROS, which may limit or prevent cancer from growing.
